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PMC:7736111 JSONTXT

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LitCovid-PD-HP

Id Subject Object Predicate Lexical cue hp_id
T1 1573-1597 Phenotype denotes impaired T cell function http://purl.obolibrary.org/obo/HP_0005435
T2 1687-1696 Phenotype denotes pneumonia http://purl.obolibrary.org/obo/HP_0002090
T3 3532-3565 Phenotype denotes impaired adaptive immune response http://purl.obolibrary.org/obo/HP_0031404
T4 4251-4271 Phenotype denotes respiratory distress http://purl.obolibrary.org/obo/HP_0002098
T5 4384-4409 Phenotype denotes cytokine release syndrome http://purl.obolibrary.org/obo/HP_0033041
T6 4415-4430 Phenotype denotes lymphocytopenia http://purl.obolibrary.org/obo/HP_0001888
T7 5266-5280 Phenotype denotes cytokine storm http://purl.obolibrary.org/obo/HP_0033041
T8 10200-10208 Phenotype denotes melanoma http://purl.obolibrary.org/obo/HP_0002861
T9 15160-15168 Phenotype denotes melanoma http://purl.obolibrary.org/obo/HP_0002861
T10 34400-34409 Phenotype denotes hepatitis http://purl.obolibrary.org/obo/HP_0012115
T11 35251-35273 Phenotype denotes respiratory infections http://purl.obolibrary.org/obo/HP_0011947
T12 39071-39087 Phenotype denotes severe infection http://purl.obolibrary.org/obo/HP_0032169
T13 45262-45279 Phenotype denotes acute lung injury http://www.orpha.net/ORDO/Orphanet_178320
T14 58422-58446 Phenotype denotes interstitial pneumonitis http://purl.obolibrary.org/obo/HP_0006515
T15 70234-70249 Phenotype denotes lymphocytopenia http://purl.obolibrary.org/obo/HP_0001888
T16 72313-72327 Phenotype denotes cytokine storm http://purl.obolibrary.org/obo/HP_0033041
T17 72360-72374 Phenotype denotes Cytokine Storm http://purl.obolibrary.org/obo/HP_0033041
T18 77554-77569 Phenotype denotes Lymphocytopenia http://purl.obolibrary.org/obo/HP_0001888
T19 78565-78580 Phenotype denotes lymphocytopenia http://purl.obolibrary.org/obo/HP_0001888
T20 90245-90265 Phenotype denotes autoimmune condition http://purl.obolibrary.org/obo/HP_0002960
T21 98096-98113 Phenotype denotes acute lung injury http://www.orpha.net/ORDO/Orphanet_178320
T22 106241-106250 Phenotype denotes pneumonia http://purl.obolibrary.org/obo/HP_0002090
T23 107917-107932 Phenotype denotes Lymphocytopenia http://purl.obolibrary.org/obo/HP_0001888
T24 108010-108025 Phenotype denotes lymphocytopenia http://purl.obolibrary.org/obo/HP_0001888
T25 108384-108399 Phenotype denotes lymphocytopenia http://purl.obolibrary.org/obo/HP_0001888
T26 108540-108555 Phenotype denotes lymphocytopenia http://purl.obolibrary.org/obo/HP_0001888
T27 109482-109497 Phenotype denotes lymphocytopenia http://purl.obolibrary.org/obo/HP_0001888
T28 109971-109986 Phenotype denotes lymphocytopenia http://purl.obolibrary.org/obo/HP_0001888
T29 110742-110757 Phenotype denotes lymphocytopenia http://purl.obolibrary.org/obo/HP_0001888
T30 113090-113105 Phenotype denotes lymphocytopenia http://purl.obolibrary.org/obo/HP_0001888
T31 113833-113850 Phenotype denotes chronic infection http://purl.obolibrary.org/obo/HP_0031035
T32 114068-114084 Phenotype denotes immunodeficiency http://purl.obolibrary.org/obo/HP_0002721
T33 115017-115032 Phenotype denotes lymphocytopenia http://purl.obolibrary.org/obo/HP_0001888
T34 116250-116265 Phenotype denotes lymphocytopenia http://purl.obolibrary.org/obo/HP_0001888
T35 116740-116755 Phenotype denotes lymphocytopenia http://purl.obolibrary.org/obo/HP_0001888
T36 116821-116836 Phenotype denotes lymphocytopenia http://purl.obolibrary.org/obo/HP_0001888
T37 117276-117291 Phenotype denotes lymphocytopenia http://purl.obolibrary.org/obo/HP_0001888
T38 117658-117673 Phenotype denotes lymphocytopenia http://purl.obolibrary.org/obo/HP_0001888
T39 118325-118339 Phenotype denotes cytokine storm http://purl.obolibrary.org/obo/HP_0033041
T40 118606-118622 Phenotype denotes highly sensitive http://purl.obolibrary.org/obo/HP_0041092
T41 118777-118791 Phenotype denotes Cytokine Storm http://purl.obolibrary.org/obo/HP_0033041
T42 118865-118879 Phenotype denotes cytokine storm http://purl.obolibrary.org/obo/HP_0033041
T43 118881-118883 Phenotype denotes CS http://purl.obolibrary.org/obo/HP_0033041
T44 119020-119022 Phenotype denotes CS http://purl.obolibrary.org/obo/HP_0033041
T45 119241-119243 Phenotype denotes CS http://purl.obolibrary.org/obo/HP_0033041
T46 119267-119292 Phenotype denotes cytokine release syndrome http://purl.obolibrary.org/obo/HP_0033041
T47 119440-119442 Phenotype denotes CS http://purl.obolibrary.org/obo/HP_0033041
T48 121454-121466 Phenotype denotes hypertension http://purl.obolibrary.org/obo/HP_0000822
T49 124733-124735 Phenotype denotes CS http://purl.obolibrary.org/obo/HP_0033041
T50 124989-125004 Phenotype denotes lymphocytopenia http://purl.obolibrary.org/obo/HP_0001888
T51 125009-125023 Phenotype denotes cytokine storm http://purl.obolibrary.org/obo/HP_0033041
T52 125205-125220 Phenotype denotes lymphocytopenia http://purl.obolibrary.org/obo/HP_0001888
T53 126045-126060 Phenotype denotes lymphocytopenia http://purl.obolibrary.org/obo/HP_0001888
T54 128049-128064 Phenotype denotes Lymphocytopenia http://purl.obolibrary.org/obo/HP_0001888
T55 130851-130866 Phenotype denotes Lymphocytopenia http://purl.obolibrary.org/obo/HP_0001888
T56 133188-133214 Phenotype denotes increase in platelet count http://purl.obolibrary.org/obo/HP_0001894
T57 133240-133267 Phenotype denotes increase in total bilirubin http://purl.obolibrary.org/obo/HP_0003573
T58 134503-134515 Phenotype denotes Leukocytosis http://purl.obolibrary.org/obo/HP_0001974
T59 134640-134655 Phenotype denotes lymphocytopenia http://purl.obolibrary.org/obo/HP_0001888
T60 135276-135291 Phenotype denotes lymphocytopenia http://purl.obolibrary.org/obo/HP_0001888
T61 136683-136699 Phenotype denotes multiple myeloma http://purl.obolibrary.org/obo/HP_0006775
T62 137327-137342 Phenotype denotes lymphocytopenia http://purl.obolibrary.org/obo/HP_0001888
T63 139155-139170 Phenotype denotes lymphocytopenia http://purl.obolibrary.org/obo/HP_0001888
T64 139849-139860 Phenotype denotes Lymphopenia http://purl.obolibrary.org/obo/HP_0001888
T65 139862-139874 Phenotype denotes neutrophilia http://purl.obolibrary.org/obo/HP_0011897
T66 139880-139896 Phenotype denotes thrombocytopenia http://purl.obolibrary.org/obo/HP_0001873
T67 142847-142867 Phenotype denotes Respiratory Distress http://purl.obolibrary.org/obo/HP_0002098
T68 142993-143007 Phenotype denotes cytokine storm http://purl.obolibrary.org/obo/HP_0033041
T69 143013-143028 Phenotype denotes lymphocytopenia http://purl.obolibrary.org/obo/HP_0001888
T70 144282-144305 Phenotype denotes diffuse alveolar damage http://purl.obolibrary.org/obo/HP_0033006
T71 144307-144310 Phenotype denotes DAD http://purl.obolibrary.org/obo/HP_0033006
T72 144343-144355 Phenotype denotes desquamation http://purl.obolibrary.org/obo/HP_0040189
T73 144473-144488 Phenotype denotes pulmonary edema http://purl.obolibrary.org/obo/HP_0100598
T74 146550-146555 Phenotype denotes edema http://purl.obolibrary.org/obo/HP_0000969
T75 147497-147509 Phenotype denotes desquamation http://purl.obolibrary.org/obo/HP_0040189
T76 147649-147673 Phenotype denotes microvesicular steatosis http://purl.obolibrary.org/obo/HP_0001414
T77 148165-148168 Phenotype denotes DAD http://purl.obolibrary.org/obo/HP_0033006
T78 148269-148274 Phenotype denotes edema http://purl.obolibrary.org/obo/HP_0000969
T79 149494-149497 Phenotype denotes DAD http://purl.obolibrary.org/obo/HP_0033006
T80 150965-150980 Phenotype denotes lymphocytopenia http://purl.obolibrary.org/obo/HP_0001888
T81 151749-151763 Phenotype denotes cytokine storm http://purl.obolibrary.org/obo/HP_0033041
T82 155019-155024 Phenotype denotes Tumor http://purl.obolibrary.org/obo/HP_0002664
T83 155050-155055 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664

LitCovid-PubTator

Id Subject Object Predicate Lexical cue tao:has_database_id
2 0-8 Disease denotes COVID-19 MESH:C000657245
3 71-76 Disease denotes Death MESH:D003643
19 149-159 Species denotes SARS-CoV-2 Tax:2697049
20 202-210 Species denotes patients Tax:9606
21 236-244 Species denotes patients Tax:9606
22 553-561 Species denotes patients Tax:9606
23 753-761 Species denotes patients Tax:9606
24 1258-1268 Species denotes SARS-CoV-2 Tax:2697049
25 1186-1197 Species denotes respiratory Tax:12814
26 782-791 Species denotes SARS-CoV2 Tax:2697049
27 136-145 Disease denotes infection MESH:D007239
28 193-201 Disease denotes COVID-19 MESH:C000657245
29 544-552 Disease denotes COVID-19 MESH:C000657245
30 604-612 Disease denotes COVID-19 MESH:C000657245
31 738-752 Disease denotes critically ill MESH:D016638
32 1573-1609 Disease denotes impaired T cell function/dysfunction MESH:D003072
33 1635-1643 Disease denotes COVID-19 MESH:C000657245
64 4073-4077 Gene denotes IL-6 Gene:3569
65 4450-4453 Gene denotes CD4 Gene:920
66 4456-4459 Gene denotes CD8 Gene:925
67 1843-1853 Species denotes SARS-CoV-2 Tax:2697049
68 2065-2075 Species denotes SARS-CoV-2 Tax:2697049
69 2152-2162 Species denotes SARS-CoV-2 Tax:2697049
70 2236-2244 Species denotes SARS-CoV Tax:694009
71 2484-2497 Species denotes coronaviruses Tax:11118
72 3357-3365 Species denotes patients Tax:9606
73 3740-3748 Species denotes patients Tax:9606
74 3831-3839 Species denotes patients Tax:9606
75 4226-4234 Species denotes patients Tax:9606
76 4656-4664 Species denotes patients Tax:9606
77 4987-4995 Species denotes patients Tax:9606
78 5302-5310 Species denotes patients Tax:9606
79 2895-2906 Species denotes respiratory Tax:12814
80 1687-1696 Disease denotes pneumonia MESH:D011014
81 1818-1826 Disease denotes COVID-19 MESH:C000657245
82 2834-2843 Disease denotes infection MESH:D007239
83 3304-3313 Disease denotes infection MESH:D007239
84 3731-3739 Disease denotes COVID-19 MESH:C000657245
85 4217-4225 Disease denotes COVID-19 MESH:C000657245
86 4245-4280 Disease denotes acute respiratory distress syndrome MESH:D012128
87 4282-4286 Disease denotes ARDS MESH:D012128
88 4304-4322 Disease denotes hyper inflammation MESH:D007249
89 4415-4430 Disease denotes lymphocytopenia MESH:D008231
90 4606-4628 Disease denotes multiple organ failure MESH:D009102
91 4978-4986 Disease denotes COVID-19 MESH:C000657245
92 5285-5289 Disease denotes ARDS MESH:D012128
93 5293-5301 Disease denotes COVID-19 MESH:C000657245
107 5555-5559 Gene denotes ACE2 Gene:59272
108 5650-5657 Gene denotes TMPRSS2 Gene:7113
109 5714-5719 Gene denotes furin Gene:5045
110 6655-6659 Gene denotes ACE2 Gene:59272
111 5585-5586 Gene denotes S Gene:43740568
112 5415-5425 Species denotes SARS-CoV-2 Tax:2697049
113 5448-5456 Species denotes SARS-CoV Tax:694009
114 5742-5752 Species denotes SARS-CoV-2 Tax:2697049
115 6112-6120 Species denotes SARS-CoV Tax:694009
116 6242-6252 Species denotes SARS-CoV-2 Tax:2697049
117 6746-6756 Species denotes SARS-CoV-2 Tax:2697049
118 6764-6772 Species denotes SARS-CoV Tax:694009
119 6226-6234 Disease denotes infected MESH:D007239
134 7071-7075 Gene denotes ACE2 Gene:59272
135 7228-7232 Gene denotes ACE2 Gene:59272
136 7315-7319 Gene denotes ACE2 Gene:59272
137 7394-7401 Gene denotes TMPRSS2 Gene:7113
138 7403-7410 Gene denotes TMPRSS2 Gene:7113
139 8174-8178 Gene denotes ACE2 Gene:59272
140 7864-7869 Gene denotes furin Gene:5045
141 6867-6877 Species denotes SARS-CoV-2 Tax:2697049
142 6938-6946 Species denotes SARS-CoV Tax:694009
143 6970-6980 Species denotes SARS-CoV-2 Tax:2697049
144 7042-7052 Species denotes SARS-CoV-2 Tax:2697049
145 7795-7805 Species denotes SARS-CoV-2 Tax:2697049
146 7920-7930 Species denotes SARS-CoV-2 Tax:2697049
147 8004-8013 Disease denotes infection MESH:D007239
156 8500-8505 Species denotes human Tax:9606
157 8516-8529 Species denotes coronaviruses Tax:11118
158 8531-8535 Species denotes CoVs Tax:11118
159 8757-8761 Species denotes CoVs Tax:11118
160 8944-8948 Species denotes CoVs Tax:11118
161 9108-9116 Species denotes patients Tax:9606
162 9344-9354 Species denotes SARS-CoV-2 Tax:2697049
163 9154-9172 Disease denotes SARS-CoV infection MESH:C000657245
174 9839-9862 Gene denotes cyclic GMP–AMP synthase Gene:115004
175 9875-9905 Gene denotes retinoic acid-inducible gene I Gene:23586
176 9985-9989 Gene denotes TLR3 Gene:7098
177 9991-9995 Gene denotes TLR7 Gene:51284
178 9997-10001 Gene denotes TLR8 Gene:51311
179 10003-10007 Gene denotes TLR9 Gene:54106
180 9442-9450 Species denotes SARS-CoV Tax:694009
181 9455-9465 Species denotes SARS-CoV-2 Tax:2697049
182 10088-10097 Species denotes SARS-CoVs Tax:694009
183 9907-9912 Gene denotes RIG-I Gene:23586
238 10193-10198 Gene denotes RIG-I Gene:23586
239 10200-10242 Gene denotes melanoma differentiation-associated gene 5 Gene:64135
240 10244-10248 Gene denotes MDA5 Gene:64135
241 10320-10325 Gene denotes DHX58 Gene:79132
242 10341-10345 Gene denotes LGP2 Gene:79132
243 10396-10401 Gene denotes RIG-I Gene:23586
244 10445-10449 Gene denotes MDA5 Gene:64135
245 10563-10568 Gene denotes RIG-I Gene:23586
246 10573-10577 Gene denotes MDA5 Gene:64135
247 10665-10670 Gene denotes RIG-I Gene:23586
248 10726-10732 Gene denotes TRIM25 Gene:7706
249 10797-10801 Gene denotes MDA5 Gene:64135
250 10871-10898 Gene denotes poly (rC) binding protein 2 Gene:5094
251 10900-10905 Gene denotes PCBP2 Gene:5094
252 10928-10932 Gene denotes AIP4 Gene:83737
253 10933-10937 Gene denotes ITCH Gene:83737
254 10939-10971 Gene denotes Atrophin 1 Interacting Protein 4 Gene:83737
255 10985-10989 Gene denotes ITCH Gene:83737
256 11011-11015 Gene denotes LGP2 Gene:79132
257 11066-11071 Gene denotes RIG-1 Gene:5920
258 11076-11080 Gene denotes MDA5 Gene:64135
259 11113-11118 Gene denotes RIG-I Gene:23586
260 11123-11127 Gene denotes MDA5 Gene:64135
261 11193-11234 Gene denotes mitochondrial antiviral signaling protein Gene:57506
262 11236-11240 Gene denotes MAVS Gene:57506
263 11295-11299 Gene denotes IRF3 Gene:3661
264 11300-11304 Gene denotes IRF7 Gene:3665
265 11349-11355 Gene denotes IRF3/7 Gene:3661
266 11419-11422 Gene denotes IFN Gene:3439
267 11543-11547 Gene denotes MAVS Gene:57506
268 11581-11584 Gene denotes IFN Gene:3439
269 11595-11599 Gene denotes IRF3 Gene:3661
270 11604-11608 Gene denotes IRF7 Gene:3665
271 11714-11719 Gene denotes NF κB Gene:4790
272 11891-11896 Gene denotes NF κB Gene:4790
273 11945-11951 Gene denotes IRF3/7 Gene:3661
274 11955-11960 Gene denotes NF κB Gene:4790
275 12290-12294 Gene denotes TLR3 Gene:142980
276 12299-12303 Gene denotes TLR4 Gene:21898
277 12499-12504 Gene denotes MYD88 Gene:17874
278 12694-12698 Gene denotes TLR7 Gene:51284
279 12700-12704 Gene denotes TLR8 Gene:51311
280 12710-12714 Gene denotes TLR9 Gene:54106
281 12741-12745 Gene denotes TLR4 Gene:7099
282 12163-12167 Species denotes mice Tax:10090
283 12313-12317 Species denotes mice Tax:10090
284 12430-12434 Species denotes Mice Tax:10090
285 12219-12228 Disease denotes infection MESH:D007239
286 12270-12288 Disease denotes SARS-CoV infection MESH:C000657245
287 12367-12378 Disease denotes lung damage MESH:D008171
288 12392-12401 Disease denotes mortality MESH:D003643
289 12601-12610 Disease denotes mortality MESH:D003643
290 12821-12843 Disease denotes attenuated lung damage MESH:C538265
291 12880-12897 Disease denotes SARS-CoV infected MESH:C000657245
355 13275-13280 Gene denotes RIG-I Gene:23586
356 13285-13289 Gene denotes MDA5 Gene:64135
357 13449-13454 Gene denotes RIG-I Gene:23586
358 13459-13463 Gene denotes MDA5 Gene:64135
359 13525-13529 Gene denotes MAVS Gene:57506
360 13555-13559 Gene denotes MAVS Gene:57506
361 13610-13621 Gene denotes TRAF2/3/5/6 Gene:7186
362 13660-13664 Gene denotes MAVS Gene:57506
363 13731-13737 Gene denotes IRF3/7 Gene:3661
364 13745-13750 Gene denotes NF-κB Gene:4790
365 13759-13763 Gene denotes MAVS Gene:57506
366 13793-13800 Gene denotes TRAF5/6 Gene:7188
367 13806-13811 Gene denotes TRADD Gene:8717
368 13813-13817 Gene denotes FADD Gene:8772
369 13823-13828 Gene denotes RIPK1 Gene:8737
370 13839-13844 Gene denotes NF-κB Gene:4790
371 13866-13870 Gene denotes MAVS Gene:57506
372 13876-13881 Gene denotes STING Gene:340061
373 13892-13896 Gene denotes TBK1 Gene:29110
374 13901-13905 Gene denotes IKKε Gene:9641
375 13926-13933 Gene denotes TRAF2/3 Gene:7186
376 13981-13985 Gene denotes IRF3 Gene:3661
377 13990-13994 Gene denotes IRF7 Gene:3665
378 14026-14030 Gene denotes IRF3 Gene:3661
379 14032-14036 Gene denotes IRF7 Gene:3665
380 14042-14047 Gene denotes NF-κB Gene:4790
381 14104-14107 Gene denotes IFN Gene:3439
382 14342-14345 Gene denotes JAK Gene:3716
383 14709-14715 Gene denotes TRIM25 Gene:7706
384 14739-14744 Gene denotes RIG-I Gene:23586
385 14776-14780 Gene denotes MDA5 Gene:64135
386 14797-14801 Gene denotes MAVS Gene:57506
387 14818-14823 Gene denotes RIG-I Gene:23586
388 14824-14828 Gene denotes MDA5 Gene:64135
389 14881-14885 Gene denotes IKKε Gene:9641
390 14891-14895 Gene denotes TBK1 Gene:29110
391 14934-14939 Gene denotes RIG-I Gene:23586
392 14941-14945 Gene denotes MDA5 Gene:64135
393 14951-14955 Gene denotes MAVs Gene:57506
394 15048-15051 Gene denotes IFN Gene:3439
395 15115-15120 Gene denotes RIG-I Gene:23586
396 15122-15152 Gene denotes Retinoic acid-inducible gene I Gene:23586
397 15154-15158 Gene denotes MDA5 Gene:64135
398 15160-15205 Gene denotes melanoma differentiation-associated protein 5 Gene:64135
399 15298-15302 Gene denotes FADD Gene:8772
400 15304-15339 Gene denotes FAS-associated death domain protein Gene:8772
401 15341-15344 Gene denotes IRF Gene:84676
402 15376-15382 Gene denotes IRF3/7 Gene:3661
403 15385-15390 Gene denotes TRADD Gene:8717
404 15392-15429 Gene denotes TNFR1-associated death domain protein Gene:8717
405 15431-15435 Gene denotes IKKε Gene:9641
406 15451-15456 Gene denotes RIPK1 Gene:8737
407 15458-15488 Gene denotes Receptor-interacting protein 1 Gene:8737
408 15496-15546 Gene denotes TRAF family member-associated NF-kappa-B activator Gene:10010
409 15548-15552 Gene denotes TBK1 Gene:29110
410 15554-15575 Gene denotes TANK-binding kinase 1 Gene:29110
411 15611-15617 Gene denotes TRIM25 Gene:7706
412 15619-15657 Gene denotes Tripartite motif-containing protein 25 Gene:7706
413 14561-14569 Species denotes SARS-CoV Tax:694009
414 14581-14591 Species denotes SARS-CoV-2 Tax:2697049
415 14984-14994 Species denotes SARS-CoV-2 Tax:2697049
416 15079-15086 Species denotes red box Tax:1226038
417 14162-14165 Gene denotes IFN Gene:3439
437 16060-16066 Gene denotes TLR7/8 Gene:51284
438 16457-16462 Gene denotes RIG-I Gene:23586
439 16464-16468 Gene denotes MDA5 Gene:64135
440 16474-16478 Gene denotes LGP2 Gene:79132
441 16925-16929 Gene denotes TLR7 Gene:51284
442 16934-16938 Gene denotes TLR8 Gene:51311
443 16990-16994 Gene denotes MAVS Gene:57506
444 16996-17000 Gene denotes IRF3 Gene:3661
445 17006-17010 Gene denotes IRF7 Gene:3665
446 15733-15743 Species denotes SARS-CoV-2 Tax:2697049
447 15947-15957 Species denotes SARS-CoV-2 Tax:2697049
448 16164-16174 Species denotes SARS-CoV-2 Tax:2697049
449 16197-16205 Species denotes SARS-CoV Tax:694009
450 16223-16233 Species denotes SARS-CoV-2 Tax:2697049
451 16385-16393 Species denotes patients Tax:9606
452 16506-16516 Species denotes SARS-CoV-2 Tax:2697049
453 16693-16703 Species denotes SARS-CoV-2 Tax:2697049
454 17240-17250 Species denotes SARS-CoV-2 Tax:2697049
455 15859-15868 Disease denotes infection MESH:D007239
459 17298-17303 Species denotes human Tax:9606
460 17314-17323 Species denotes SARS-CoVs Tax:694009
461 17473-17483 Species denotes SARS-CoV-2 Tax:2697049
500 17865-17871 Gene denotes TRIM25 Gene:7706
501 17906-17911 Gene denotes RIG-I Gene:23586
502 17964-17970 Gene denotes TRIM25 Gene:7706
503 18013-18018 Gene denotes RIG-I Gene:23586
504 18063-18068 Gene denotes RIG-I Gene:23586
505 18130-18135 Gene denotes IFN-β Gene:3439
506 18193-18196 Gene denotes IFN Gene:3439
507 18236-18240 Gene denotes IRF3 Gene:3661
508 18412-18416 Gene denotes IRF3 Gene:3661
509 18417-18421 Gene denotes IRF7 Gene:3665
510 18452-18457 Gene denotes RIG-I Gene:23586
511 18459-18463 Gene denotes TBK1 Gene:29110
512 18465-18469 Gene denotes IKKε Gene:9641
513 18475-18480 Gene denotes TRAF3 Gene:7187
514 18573-18577 Gene denotes Nsp1 Gene:10045
515 18587-18592 Gene denotes IFN-β Gene:3439
516 18615-18620 Gene denotes STAT1 Gene:6772
517 18844-18849 Gene denotes TRAF3 Gene:7187
518 18851-18855 Gene denotes TBK1 Gene:29110
519 18857-18861 Gene denotes IKKε Gene:9641
520 18863-18868 Gene denotes STING Gene:340061
521 18874-18878 Gene denotes IRF3 Gene:3661
522 18909-18913 Gene denotes IRF3 Gene:3661
523 18914-18918 Gene denotes IRF7 Gene:3665
524 18997-19001 Gene denotes IRF3 Gene:3661
525 19067-19071 Gene denotes ORF6 Gene:43740572
526 19130-19134 Gene denotes IRF3 Gene:3661
527 19344-19369 Gene denotes dynamin-related protein 1 Gene:10059
528 19371-19375 Gene denotes Drp1 Gene:10059
529 19432-19436 Gene denotes MAVS Gene:57506
530 19524-19529 Gene denotes PCBP2 Gene:5094
531 19534-19538 Gene denotes AIP4 Gene:83737
532 19573-19577 Gene denotes MAVS Gene:57506
533 19633-19638 Gene denotes IFN-β Gene:3439
534 17674-17682 Species denotes SARS-CoV Tax:694009
535 17939-17947 Species denotes SARS-CoV Tax:694009
536 19741-19749 Species denotes SARS-CoV Tax:694009
537 19762-19765 Gene denotes IFN Gene:3439
557 19965-19968 Gene denotes IFN Gene:3439
558 20237-20242 Gene denotes ORF3a Gene:43740569
559 20315-20318 Gene denotes IFN Gene:3439
560 20333-20338 Gene denotes NF-κB Gene:4790
561 20359-20363 Gene denotes Nsp5 Gene:92521
562 20380-20385 Gene denotes HDAC2 Gene:3066
563 20430-20433 Gene denotes IFN Gene:3439
564 20723-20727 Gene denotes ORF6 Gene:43740572
565 20823-20828 Gene denotes IFN-β Gene:3439
566 20833-20838 Gene denotes NF-κB Gene:4790
567 20919-20923 Gene denotes ORF6 Gene:43740572
568 21005-21010 Gene denotes NUP98 Gene:4928
569 21011-21015 Gene denotes RAE1 Gene:8480
570 21094-21097 Gene denotes IFN Gene:3439
571 19882-19892 Species denotes SARS-CoV-2 Tax:2697049
572 20050-20060 Species denotes SARS-CoV-2 Tax:2697049
573 20126-20136 Species denotes SARS-CoV-2 Tax:2697049
574 20892-20895 Gene denotes IFN Gene:3439
575 20777-20783 CellLine denotes HEK293 CVCL:0045
586 21196-21199 Gene denotes IFN Gene:3439
587 21574-21578 Gene denotes MDA5 Gene:64135
588 21813-21816 Gene denotes PKR Gene:5610
589 21869-21870 Gene denotes N Gene:43740575
590 21475-21486 Gene denotes ribose 2′-O
591 21220-21228 Species denotes SARS-CoV Tax:694009
592 21450-21458 Species denotes SARS-CoV Tax:694009
593 21715-21723 Species denotes SARS-CoV Tax:694009
594 21882-21892 Species denotes SARS-CoV-2 Tax:2697049
595 22031-22048 Disease denotes SARS-CoV infected MESH:C000657245
597 22511-22516 Disease denotes Death MESH:D003643
608 22782-22786 Gene denotes Nsp1 Gene:10045
609 22896-22900 Gene denotes Nsp1 Gene:10045
610 23106-23126 Gene denotes La-related protein 1 Gene:23367
611 23128-23133 Gene denotes LARP1 Gene:23367
612 23032-23033 Gene denotes N Gene:43740575
613 22522-22530 Species denotes SARS-CoV Tax:694009
614 22535-22545 Species denotes SARS-CoV-2 Tax:2697049
615 22790-22798 Species denotes SARS-CoV Tax:694009
616 23045-23055 Species denotes SARS-CoV-2 Tax:2697049
617 23255-23265 Species denotes SARS-CoV-2 Tax:2697049
628 23346-23349 Gene denotes p53 Gene:7157
629 23585-23590 Gene denotes eIF3f Gene:8665
630 24077-24080 Gene denotes Bax Gene:581
631 24085-24090 Gene denotes Bcl-2 Gene:596
632 23313-23321 Species denotes SARS-CoV Tax:694009
633 23512-23520 Species denotes SARS-CoV Tax:694009
634 24128-24136 Species denotes SARS-CoV Tax:694009
635 24140-24150 Species denotes SARS-CoV-2 Tax:2697049
636 23698-23709 Species denotes respiratory Tax:12814
637 23453-23461 Disease denotes infected MESH:D007239
647 24400-24405 Gene denotes Bcl-X Gene:598
648 24476-24481 Gene denotes ORF3a Gene:43740569
649 24613-24618 Gene denotes ORF3a Gene:43740569
650 24722-24727 Gene denotes RIPK3 Gene:11035
651 24794-24799 Gene denotes ORF3a Gene:43740569
652 24924-24933 Gene denotes caspase 8 Gene:841
653 24338-24346 Species denotes SARS-CoV Tax:694009
654 24803-24813 Species denotes SARS-CoV-2 Tax:2697049
655 24893-24899 CellLine denotes HEK293 CVCL:0045
664 25005-25010 Gene denotes ORF3a Gene:43740569
665 25282-25287 Gene denotes RIPK1 Gene:8737
666 25014-25024 Species denotes SARS-CoV-2 Tax:2697049
667 25097-25105 Species denotes SARS-CoV Tax:694009
668 25194-25204 Species denotes SARS-CoV-2 Tax:2697049
669 25235-25245 Species denotes SARS-CoV-2 Tax:2697049
670 25479-25489 Species denotes SARS-CoV-2 Tax:2697049
671 25787-25797 Species denotes SARS-CoV-2 Tax:2697049
676 25987-25990 Gene denotes IFN Gene:3439
677 25950-25960 Species denotes SARS-CoV-2 Tax:2697049
678 26223-26231 Species denotes SARS-CoV Tax:694009
679 26236-26246 Species denotes SARS-CoV-2 Tax:2697049
681 26381-26389 Disease denotes COVID-19 MESH:C000657245
686 26778-26782 Species denotes CoVs Tax:11118
687 27000-27008 Species denotes patients Tax:9606
688 26991-26999 Disease denotes COVID-19 MESH:C000657245
689 27132-27140 Disease denotes COVID-19 MESH:C000657245
698 27684-27689 Gene denotes STAT1 Gene:20846
699 27962-27967 Gene denotes IFNR1 Gene:3454
700 27699-27703 Species denotes mice Tax:10090
701 27718-27726 Species denotes SARS-CoV Tax:694009
702 27928-27936 Species denotes SARS-CoV Tax:694009
703 28001-28005 Species denotes mice Tax:10090
704 27664-27682 Disease denotes SARS-CoV infection MESH:C000657245
705 27704-27712 Disease denotes infected MESH:D007239
723 28170-28173 Gene denotes IFN Gene:3439
724 28348-28351 Gene denotes IFN Gene:3439
725 28365-28370 Gene denotes STAT1 Gene:6772
726 28669-28672 Gene denotes IFN Gene:3439
727 28792-28796 Gene denotes ACE2 Gene:59272
728 28894-28898 Gene denotes ACE2 Gene:59272
729 28295-28298 Gene denotes IFN Gene:3439
730 28196-28206 Species denotes SARS-CoV-2 Tax:2697049
731 28267-28277 Species denotes SARS-CoV-2 Tax:2697049
732 28333-28341 Species denotes SARS-CoV Tax:694009
733 28592-28600 Species denotes patients Tax:9606
734 28700-28710 Species denotes SARS-CoV-2 Tax:2697049
735 28944-28954 Species denotes SARS-CoV-2 Tax:2697049
736 28835-28846 Species denotes respiratory Tax:12814
737 28253-28261 Disease denotes infected MESH:D007239
738 28319-28327 Disease denotes infected MESH:D007239
739 28583-28591 Disease denotes COVID-19 MESH:C000657245
759 29121-29124 Gene denotes IFN Gene:3439
760 29291-29294 Gene denotes IFN Gene:3439
761 29653-29657 Gene denotes IFNA Gene:3439
762 29723-29726 Gene denotes IFN Gene:3439
763 29856-29862 Gene denotes IFNAR1 Gene:3454
764 29864-29868 Gene denotes JAK1 Gene:3716
765 29874-29878 Gene denotes TYK2 Gene:7297
766 29902-29905 Gene denotes IFN Gene:3439
767 29928-29932 Gene denotes IFNB Gene:3456
768 29987-29990 Gene denotes IFN Gene:3439
769 29082-29085 Gene denotes IFN Gene:3439
770 29002-29010 Species denotes patients Tax:9606
771 29044-29052 Species denotes patients Tax:9606
772 29486-29494 Species denotes patients Tax:9606
773 29592-29600 Species denotes patients Tax:9606
774 29754-29762 Species denotes patients Tax:9606
775 29564-29567 Gene denotes IFN Gene:3439
776 28993-29001 Disease denotes COVID-19 MESH:C000657245
777 29477-29485 Disease denotes COVID-19 MESH:C000657245
806 30234-30237 Gene denotes IFN Gene:3439
807 30328-30333 Gene denotes IFN-β Gene:3439
808 30337-30340 Gene denotes IFN Gene:3439
809 30493-30498 Gene denotes IFN-β Gene:3439
810 30502-30505 Gene denotes IFN Gene:3439
811 30566-30572 Gene denotes IFNAR1 Gene:3454
812 30576-30582 Gene denotes IFNLR1 Gene:163702
813 30683-30686 Gene denotes IFN Gene:3439
814 30764-30767 Gene denotes IFN Gene:3439
815 31023-31026 Gene denotes IFN Gene:3439
816 31132-31135 Gene denotes IFN Gene:3439
817 31256-31259 Gene denotes IFN Gene:3439
818 31453-31456 Gene denotes IFN Gene:3439
819 30801-30809 Species denotes patients Tax:9606
820 30897-30903 Species denotes people Tax:9606
821 30938-30944 Species denotes people Tax:9606
822 31286-31294 Species denotes patients Tax:9606
823 31496-31506 Species denotes SARS-CoV-2 Tax:2697049
824 31659-31667 Species denotes SARS-CoV Tax:694009
825 30365-30385 Disease denotes SARS-CoV-2 infection MESH:C000657245
826 30523-30538 Disease denotes viral infection MESH:D001102
827 30624-30643 Disease denotes SARS-CoV-2 infected MESH:C000657245
828 30878-30887 Disease denotes infection MESH:D007239
829 30975-30983 Disease denotes diabetes MESH:D003920
830 31066-31081 Disease denotes CoV-2 infection MESH:C000657245
831 31605-31614 Disease denotes mortality MESH:D003643
832 31628-31636 Disease denotes COVID-19 MESH:C000657245
833 31672-31687 Disease denotes MERS infections MESH:D018352
841 31994-32003 Disease denotes infection MESH:D007239
842 32042-32050 Disease denotes infected MESH:D007239
843 32328-32337 Disease denotes infection MESH:D007239
844 32428-32437 Disease denotes infection MESH:D007239
845 32542-32551 Disease denotes infection MESH:D007239
846 32687-32696 Disease denotes infection MESH:D007239
847 32728-32736 Disease denotes COVID-19 MESH:C000657245
861 32879-32883 Gene denotes IL-6 Gene:3569
862 33027-33040 Gene denotes IL-6 receptor Gene:3570
863 33042-33047 Gene denotes IL-6R Gene:3570
864 33057-33061 Gene denotes IL-6 Gene:3569
865 33169-33173 Gene denotes IL-6 Gene:3569
866 33258-33262 Gene denotes IL-6 Gene:3569
867 33286-33291 Gene denotes RIG-I Gene:23586
868 33328-33333 Gene denotes NF κB Gene:4790
869 33426-33431 Gene denotes TNF-α Gene:7124
870 33436-33441 Gene denotes IL-1β Gene:3552
871 33508-33512 Gene denotes IL-6 Gene:3569
872 33223-33231 Species denotes SARS-CoV Tax:694009
873 32839-32853 Disease denotes virus-infected MESH:D001102
882 33683-33687 Gene denotes IL-6 Gene:3569
883 33757-33761 Gene denotes IL-6 Gene:3569
884 33998-34002 Gene denotes IL-6 Gene:3569
885 33602-33607 Species denotes human Tax:9606
886 33650-33660 Species denotes SARS-CoV-2 Tax:2697049
887 33799-33807 Species denotes patients Tax:9606
888 33636-33644 Disease denotes infected MESH:D007239
889 33790-33798 Disease denotes COVID-19 MESH:C000657245
896 34394-34415 Species denotes mouse hepatitis virus Tax:11138
897 34424-34429 Species denotes MHV-1 Tax:137443
898 34631-34636 Species denotes mouse Tax:10090
899 34646-34654 Species denotes SARS-CoV Tax:694009
900 34380-34388 Disease denotes infected MESH:D007239
901 34531-34549 Disease denotes SARS-CoV infection MESH:C000657245
909 34726-34734 Species denotes patients Tax:9606
910 35041-35049 Species denotes SARS-CoV Tax:694009
911 35279-35294 Species denotes influenza virus Tax:11308
912 35327-35335 Species denotes SARS-CoV Tax:694009
913 34708-34725 Disease denotes SARS-CoV infected MESH:C000657245
914 34942-34957 Disease denotes viral infection MESH:D001102
915 35251-35273 Disease denotes respiratory infections MESH:D012141
921 35420-35428 Species denotes patients Tax:9606
922 35905-35913 Species denotes patients Tax:9606
923 36128-36136 Species denotes patients Tax:9606
924 35411-35419 Disease denotes COVID-19 MESH:C000657245
925 35896-35904 Disease denotes COVID-19 MESH:C000657245
931 36346-36356 Species denotes SARS-CoV-2 Tax:2697049
932 36571-36579 Species denotes SARS-CoV Tax:694009
933 36721-36731 Species denotes SARS-CoV-2 Tax:2697049
934 36317-36326 Disease denotes infection MESH:D007239
935 36446-36455 Disease denotes infection MESH:D007239
942 37391-37394 Gene denotes IFN Gene:3439
943 37102-37110 Species denotes patients Tax:9606
944 37339-37347 Species denotes patients Tax:9606
945 37562-37570 Species denotes patients Tax:9606
946 37093-37101 Disease denotes COVID-19 MESH:C000657245
947 37553-37561 Disease denotes COVID-19 MESH:C000657245
958 38026-38029 Gene denotes IFN Gene:3439
959 38324-38327 Gene denotes IFN Gene:3439
960 38801-38804 Gene denotes IFN Gene:3439
961 37933-37941 Species denotes SARS-CoV Tax:694009
962 37965-37975 Species denotes SARS-CoV-2 Tax:2697049
963 38116-38123 Species denotes patient Tax:9606
964 38173-38179 Species denotes people Tax:9606
965 38185-38193 Species denotes patients Tax:9606
966 38366-38373 Species denotes patient Tax:9606
967 38443-38451 Disease denotes COVID-19 MESH:C000657245
1001 39407-39410 Gene denotes IFN Gene:3439
1002 39546-39551 Gene denotes IFN-β Gene:3439
1003 39556-39559 Gene denotes IFN Gene:3439
1004 39775-39778 Gene denotes IFN Gene:3439
1005 39878-39881 Gene denotes IFN Gene:3439
1006 39986-39991 Gene denotes IFN-β Gene:3439
1007 40052-40058 Gene denotes IFN-α2 Gene:3440
1008 40165-40168 Gene denotes IFN Gene:3439
1009 40205-40208 Gene denotes IFN Gene:3439
1010 40263-40266 Gene denotes MX1 Gene:4599
1011 40268-40274 Gene denotes IFITM1 Gene:8519
1012 40276-40281 Gene denotes IFIT2 Gene:3433
1013 40357-40360 Gene denotes IFN Gene:3439
1014 39291-39294 Gene denotes IFN Gene:3439
1015 39039-39042 Gene denotes IFN Gene:3439
1016 39055-39063 Species denotes SARS-CoV Tax:694009
1017 39128-39138 Species denotes SARS-CoV-2 Tax:2697049
1018 39259-39269 Species denotes SARS-CoV-2 Tax:2697049
1019 39459-39467 Species denotes patients Tax:9606
1020 39572-39580 Species denotes patients Tax:9606
1021 39619-39627 Species denotes patients Tax:9606
1022 39921-39929 Species denotes patients Tax:9606
1023 40034-40042 Species denotes patients Tax:9606
1024 40129-40137 Species denotes patients Tax:9606
1025 40321-40329 Species denotes patients Tax:9606
1026 39078-39087 Disease denotes infection MESH:D007239
1027 39241-39249 Disease denotes infected MESH:D007239
1028 39435-39449 Disease denotes critically ill MESH:D016638
1029 39450-39458 Disease denotes COVID-19 MESH:C000657245
1030 39814-39822 Disease denotes COVID-19 MESH:C000657245
1031 39895-39909 Disease denotes critically ill MESH:D016638
1032 40114-40128 Disease denotes critically ill MESH:D016638
1033 40306-40320 Disease denotes critically ill MESH:D016638
1043 40648-40651 Gene denotes IFN Gene:3439
1044 40662-40666 Gene denotes ORF6 Gene:43740572
1045 40668-40672 Gene denotes ORF8 Gene:43740577
1046 40678-40679 Gene denotes N Gene:43740575
1047 40696-40701 Gene denotes IFN-β Gene:3439
1048 40706-40711 Gene denotes NF-κB Gene:4790
1049 40859-40862 Gene denotes IFN Gene:3439
1050 40940-40943 Gene denotes IFN Gene:3439
1051 40598-40608 Species denotes SARS-CoV-2 Tax:2697049
1084 41022-41025 Gene denotes IFN Gene:3439
1085 41187-41190 Gene denotes IFN Gene:3439
1086 41558-41562 Gene denotes TLR3 Gene:7098
1087 41568-41572 Gene denotes IRF7 Gene:3665
1088 41735-41738 Gene denotes IFN Gene:3439
1089 41910-41914 Gene denotes TLR7 Gene:51284
1090 41949-41952 Gene denotes IFN Gene:3439
1091 42013-42017 Gene denotes IRF7 Gene:3665
1092 42019-42024 Gene denotes IFNB1 Gene:3456
1093 42030-42035 Gene denotes ISG15 Gene:9636
1094 42070-42075 Gene denotes IFN-γ Gene:3458
1095 42120-42123 Gene denotes IFN Gene:3439
1096 42212-42215 Gene denotes IFN Gene:3439
1097 42287-42290 Gene denotes IFN Gene:3439
1098 42316-42319 Gene denotes IFN Gene:3439
1099 41137-41140 Gene denotes IFN Gene:3439
1100 42450-42453 Gene denotes IFN Gene:3439
1101 41229-41237 Species denotes patients Tax:9606
1102 41351-41354 Species denotes men Tax:9606
1103 41360-41365 Species denotes women Tax:9606
1104 41410-41413 Species denotes men Tax:9606
1105 41633-41641 Species denotes Patients Tax:9606
1106 41674-41682 Species denotes patients Tax:9606
1107 41815-41823 Species denotes patients Tax:9606
1108 41970-41978 Species denotes patients Tax:9606
1109 42731-42739 Species denotes patients Tax:9606
1110 42855-42865 Species denotes SARS-CoV-2 Tax:2697049
1111 42882-42885 Gene denotes IFN Gene:3439
1112 41417-41425 Disease denotes COVID-19 MESH:C000657245
1113 41766-41786 Disease denotes SARS-CoV-2 infection MESH:C000657245
1114 42405-42413 Disease denotes COVID-19 MESH:C000657245
1115 42722-42730 Disease denotes COVID-19 MESH:C000657245
1122 43242-43245 Gene denotes IFN Gene:3439
1123 43106-43109 Gene denotes IFN Gene:3439
1124 43037-43045 Species denotes SARS-CoV Tax:694009
1125 43133-43141 Species denotes patients Tax:9606
1126 43124-43132 Disease denotes COVID-19 MESH:C000657245
1127 43283-43291 Disease denotes COVID-19 MESH:C000657245
1131 43497-43500 Gene denotes IFN Gene:3439
1132 43715-43723 Disease denotes infected MESH:D007239
1133 43757-43765 Disease denotes necrotic MESH:D009336
1160 44437-44460 Gene denotes high-mobility group box Gene:6749
1161 44474-44479 Gene denotes HMGB1 Gene:3146
1162 44485-44489 Gene denotes S100 Gene:6271
1163 44553-44558 Gene denotes HMGB1 Gene:3146
1164 44576-44580 Gene denotes TLR4 Gene:7099
1165 44603-44608 Gene denotes NF-κB Gene:4790
1166 44675-44680 Gene denotes HMGB1 Gene:3146
1167 44711-44718 Gene denotes TREM1/2 Gene:54210
1168 44724-44769 Gene denotes receptors for advanced glycation end products Gene:177
1169 44771-44775 Gene denotes RAGE Gene:177
1170 44804-44809 Gene denotes NF-κB Gene:4790
1171 44909-44913 Gene denotes TLR4 Gene:7099
1172 44918-44922 Gene denotes RAGE Gene:177
1173 45117-45122 Gene denotes HMGB1 Gene:3146
1174 45224-45230 Gene denotes S100A9 Gene:6280
1175 45385-45390 Gene denotes HMGB1 Gene:3146
1176 44846-44850 Gene denotes S100 Gene:6271
1177 45246-45254 Species denotes patients Tax:9606
1178 45417-45425 Species denotes patients Tax:9606
1179 45047-45058 Species denotes respiratory Tax:12814
1180 45296-45307 Species denotes respiratory Tax:12814
1181 44232-44248 Disease denotes viral infections MESH:D001102
1182 44380-44394 Disease denotes virus-infected MESH:D001102
1183 45135-45146 Disease denotes lung injury MESH:D055370
1184 45268-45279 Disease denotes lung injury MESH:D055370
1185 45408-45416 Disease denotes COVID-19 MESH:C000657245
1197 45671-45677 Gene denotes S100A8 Gene:6279
1198 45679-45685 Gene denotes S100A9 Gene:6280
1199 45691-45698 Gene denotes S100A12 Gene:6283
1200 46489-46494 Gene denotes HMGB1 Gene:3146
1201 45750-45758 Species denotes patients Tax:9606
1202 45996-46004 Species denotes patients Tax:9606
1203 46279-46287 Species denotes patients Tax:9606
1204 45741-45749 Disease denotes COVID-19 MESH:C000657245
1205 45987-45995 Disease denotes COVID-19 MESH:C000657245
1206 46023-46044 Disease denotes inflammatory diseases MESH:D007249
1207 46270-46278 Disease denotes COVID-19 MESH:C000657245
1236 46684-46688 Gene denotes IL-6 Gene:3569
1237 46879-46884 Gene denotes TNF-α Gene:7124
1238 46886-46890 Gene denotes IL-8 Gene:3576
1239 46892-46897 Gene denotes IL-10 Gene:3586
1240 46899-46905 Gene denotes GM-CSF Gene:1437
1241 46907-46913 Gene denotes CXCL10 Gene:3627
1242 46919-46923 Gene denotes CCL5 Gene:6352
1243 47272-47277 Gene denotes CCL20 Gene:6364
1244 47279-47284 Gene denotes CXCL1 Gene:2919
1245 47286-47291 Gene denotes IL-1B Gene:3553
1246 47293-47297 Gene denotes IL-6 Gene:3569
1247 47299-47304 Gene denotes CXCL3 Gene:2921
1248 47306-47311 Gene denotes CXCL5 Gene:6374
1249 47313-47318 Gene denotes CXCL6 Gene:6372
1250 47320-47325 Gene denotes CXCL2 Gene:2920
1251 47327-47333 Gene denotes CXCL16 Gene:58191
1252 47339-47344 Gene denotes TNF-α Gene:7124
1253 46754-46762 Species denotes SARS-CoV Tax:694009
1254 46767-46777 Species denotes SARS-CoV-2 Tax:2697049
1255 47016-47024 Species denotes SARS-CoV Tax:694009
1256 47183-47188 Species denotes human Tax:9606
1257 47232-47242 Species denotes SARS-CoV-2 Tax:2697049
1258 46542-46556 Disease denotes virus infected MESH:D001102
1259 46740-46748 Disease denotes infected MESH:D007239
1260 46936-46944 Disease denotes infected MESH:D007239
1261 47029-47050 Disease denotes SARS-CoV-2 infections MESH:C000657245
1262 47218-47226 Disease denotes infected MESH:D007239
1263 47393-47413 Disease denotes SARS-CoV-2 infection MESH:C000657245
1286 47970-47975 Gene denotes TNF-α Gene:7124
1287 47977-47982 Gene denotes IL-1β Gene:3552
1288 47988-47992 Gene denotes IL-6 Gene:3569
1289 48334-48339 Gene denotes STAT1 Gene:6772
1290 49507-49511 Gene denotes IL-6 Gene:3569
1291 49516-49521 Gene denotes IL-1β Gene:3552
1292 47790-47798 Species denotes SARS-CoV Tax:694009
1293 48146-48154 Species denotes SARS-CoV Tax:694009
1294 48568-48576 Species denotes patients Tax:9606
1295 48678-48686 Species denotes patients Tax:9606
1296 48880-48888 Species denotes patients Tax:9606
1297 49154-49162 Species denotes patients Tax:9606
1298 48016-48020 Disease denotes ARDS MESH:D012128
1299 48132-48140 Disease denotes infected MESH:D007239
1300 48299-48317 Disease denotes SARS-CoV infection MESH:C000657245
1301 48398-48420 Disease denotes attenuated lung damage MESH:C538265
1302 48550-48567 Disease denotes SARS-CoV infected MESH:C000657245
1303 48669-48677 Disease denotes COVID-19 MESH:C000657245
1304 48871-48879 Disease denotes COVID-19 MESH:C000657245
1305 49139-49153 Disease denotes critically ill MESH:D016638
1306 49176-49206 Disease denotes macrophage activation syndrome MESH:D055501
1307 49376-49384 Disease denotes COVID-19 MESH:C000657245
1317 50078-50083 Gene denotes TNF-α Gene:7124
1318 50085-50089 Gene denotes IL-6 Gene:3569
1319 50091-50096 Gene denotes IL-1β Gene:3552
1320 50098-50102 Gene denotes IL-7 Gene:3574
1321 50104-50109 Gene denotes IL-23 Gene:51561
1322 50318-50326 Gene denotes CCL2/3/4 Gene:6347
1323 50328-50336 Gene denotes CXCL1-13 Gene:2919
1324 49709-49718 Disease denotes infection MESH:D007239
1325 49935-49944 Disease denotes infection MESH:D007239
1329 50829-50837 Species denotes patients Tax:9606
1330 50506-50514 Disease denotes COVID-19 MESH:C000657245
1331 50820-50828 Disease denotes COVID-19 MESH:C000657245
1346 51332-51340 Species denotes SARS-CoV Tax:694009
1347 51341-51349 Species denotes patients Tax:9606
1348 51450-51458 Species denotes patients Tax:9606
1349 51774-51782 Species denotes patients Tax:9606
1350 51952-51960 Species denotes patients Tax:9606
1351 52060-52068 Species denotes patients Tax:9606
1352 52460-52468 Species denotes patients Tax:9606
1353 51121-51136 Disease denotes viral infection MESH:D001102
1354 51230-51238 Disease denotes infected MESH:D007239
1355 51441-51449 Disease denotes COVID-19 MESH:C000657245
1356 52046-52049 Disease denotes LRS MESH:C537873
1357 52051-52059 Disease denotes COVID-19 MESH:C000657245
1358 52167-52170 Disease denotes LRS MESH:C537873
1359 52558-52566 Disease denotes COVID-19 MESH:C000657245
1383 53037-53041 Gene denotes CCR7 Gene:1236
1384 63660-63663 Gene denotes CD4 Gene:920
1385 63669-63672 Gene denotes CD8 Gene:925
1397 147248-147256 Species denotes patients Tax:9606
1398 150979-150989 Species denotes a and acti Tax:2697049
1399 151081-151089 Species denotes ers. Fur Tax:9606
1401 147239-147247 Disease denotes COVID-19 MESH:C000657245
1402 150929-150947 Disease denotes tients has remaine MESH:C000657245
1403 151057-151071 Disease denotes exhausted T ce MESH:D016638
1404 151072-151080 Disease denotes ls in ot MESH:C000657245
1405 151157-151166 Disease denotes infection MESH:D007239
1407 54277-54285 Disease denotes COVID-19 MESH:C000657245
1413 54866-54873 Species denotes patient Tax:9606
1414 54411-54426 Disease denotes viral infection MESH:D001102
1415 54480-54489 Disease denotes infection MESH:D007239
1416 54516-54524 Disease denotes infected MESH:D007239
1417 54772-54780 Disease denotes COVID-19 MESH:C000657245
1437 55490-55493 Gene denotes CD4 Gene:920
1438 55542-55545 Gene denotes CD4 Gene:920
1439 55580-55583 Gene denotes CD4 Gene:920
1440 55612-55615 Gene denotes TH1 Gene:51497
1441 55928-55932 Gene denotes IL-4 Gene:3565
1442 55937-55941 Gene denotes IL-5 Gene:3567
1443 56077-56082 Gene denotes IL-17 Gene:3605
1444 55673-55676 Gene denotes TH1 Gene:51497
1445 55879-55887 Species denotes patients Tax:9606
1446 56040-56048 Species denotes patients Tax:9606
1447 56232-56240 Species denotes patients Tax:9606
1448 56369-56376 Species denotes patient Tax:9606
1449 55835-55838 Chemical denotes TH2
1450 55107-55121 Disease denotes virus-infected MESH:D001102
1451 55283-55291 Disease denotes infected MESH:D007239
1452 55729-55747 Disease denotes SARS-CoV infection MESH:C000657245
1453 55870-55878 Disease denotes COVID-19 MESH:C000657245
1454 56223-56231 Disease denotes COVID-19 MESH:C000657245
1455 56269-56279 Disease denotes infections MESH:D007239
1491 56464-56469 Gene denotes IFN-γ Gene:3458
1492 56526-56532 Gene denotes B7-1/2 Gene:941
1493 56551-56555 Gene denotes IL-6 Gene:3569
1494 56716-56720 Gene denotes CCL3 Gene:6348
1495 56722-56726 Gene denotes CCL4 Gene:6351
1496 56728-56732 Gene denotes CCL5 Gene:6352
1497 56734-56738 Gene denotes CCL8 Gene:6355
1498 56832-56836 Gene denotes IL-2 Gene:3558
1499 56838-56843 Gene denotes IFN-γ Gene:3458
1500 56856-56861 Gene denotes TNF-α Gene:7124
1501 56956-56959 Gene denotes CD8 Gene:925
1502 57097-57100 Gene denotes CD4 Gene:920
1503 57111-57115 Gene denotes IL-2 Gene:3558
1504 57136-57139 Gene denotes CD4 Gene:920
1505 57269-57272 Gene denotes CD8 Gene:925
1506 57333-57336 Gene denotes CD4 Gene:920
1507 57453-57456 Gene denotes CD8 Gene:925
1508 57603-57607 Gene denotes CCL3 Gene:6348
1509 57609-57613 Gene denotes CCL4 Gene:6351
1510 57615-57619 Gene denotes CCL5 Gene:6352
1511 57621-57626 Gene denotes CXCL9 Gene:4283
1512 57632-57638 Gene denotes CXCL10 Gene:3627
1513 58062-58067 Gene denotes IFN-γ Gene:3458
1514 58072-58077 Gene denotes TNF-α Gene:7124
1515 56741-56744 Gene denotes TH1 Gene:51497
1516 56417-56420 Gene denotes TH1 Gene:51497
1517 56407-56415 Species denotes SARS-CoV Tax:694009
1518 58154-58158 Species denotes CoVs Tax:11118
1519 57378-57381 Gene denotes IFN Gene:3439
1520 56385-56401 Disease denotes viral infections MESH:D001102
1521 56780-56789 Disease denotes infection MESH:D007239
1522 56900-56919 Disease denotes SARS-CoV infections MESH:C000657245
1523 57661-57669 Disease denotes infected MESH:D007239
1524 57733-57741 Disease denotes infected MESH:D007239
1525 58141-58150 Disease denotes infection MESH:D007239
1539 58268-58271 Gene denotes CD4 Gene:920
1540 58363-58366 Gene denotes CD4 Gene:920
1541 59013-59016 Gene denotes CD4 Gene:920
1542 59024-59027 Gene denotes CD8 Gene:925
1543 58693-58696 Gene denotes CD4 Gene:920
1544 58702-58705 Gene denotes CD8 Gene:925
1545 58550-58553 Gene denotes CD8 Gene:925
1546 58541-58544 Gene denotes CD4 Gene:920
1547 58282-58290 Species denotes SARS-CoV Tax:694009
1548 58732-58740 Species denotes patients Tax:9606
1549 58435-58446 Disease denotes pneumonitis MESH:D011014
1550 58864-58882 Disease denotes SARS-CoV infection MESH:C000657245
1551 59083-59101 Disease denotes SARS-CoV infection MESH:C000657245
1567 59159-59162 Gene denotes CD4 Gene:920
1568 59168-59171 Gene denotes CD8 Gene:925
1569 59288-59291 Gene denotes CD4 Gene:920
1570 59355-59359 Gene denotes IL-2 Gene:3558
1571 59361-59366 Gene denotes IL-21 Gene:59067
1572 59393-59398 Gene denotes CD40L Gene:959
1573 59446-59449 Gene denotes CD8 Gene:925
1574 59519-59522 Gene denotes CD8 Gene:925
1575 59548-59553 Gene denotes IL-10 Gene:3586
1576 59591-59594 Gene denotes CD4 Gene:920
1577 59600-59603 Gene denotes CD8 Gene:925
1578 59669-59677 Species denotes patients Tax:9606
1579 59256-59261 Chemical denotes TCR-p
1580 59236-59245 Disease denotes infection MESH:D007239
1581 59651-59668 Disease denotes SARS-CoV infected MESH:C000657245
1587 60231-60241 Species denotes SARS-CoV-2 Tax:2697049
1588 60570-60578 Species denotes Patients Tax:9606
1589 59979-59988 Disease denotes infection MESH:D007239
1590 60388-60396 Disease denotes COVID-19 MESH:C000657245
1591 60561-60569 Disease denotes COVID-19 MESH:C000657245
1608 61065-61068 Gene denotes CD4 Gene:920
1609 61148-61153 Gene denotes CXCR5 Gene:643
1610 61158-61163 Gene denotes IL-21 Gene:59067
1611 61188-61192 Gene denotes CCR7 Gene:1236
1612 61194-61199 Gene denotes IFN-γ Gene:3458
1613 61201-61205 Gene denotes IL-4 Gene:3565
1614 61211-61216 Gene denotes IL-17 Gene:3605
1615 61340-61345 Gene denotes CD40L Gene:959
1616 61489-61494 Gene denotes CD40L Gene:959
1617 61535-61540 Gene denotes IL-21 Gene:59067
1618 61618-61622 Gene denotes IL-6 Gene:3569
1619 61627-61632 Gene denotes IL-27 Gene:246778
1620 60669-60685 Disease denotes viral infections MESH:D001102
1621 60968-60976 Disease denotes COVID-19 MESH:C000657245
1622 61832-61850 Disease denotes SARS-CoV infection MESH:C000657245
1623 62262-62274 Disease denotes cytotoxicity MESH:D064420
1625 62621-62629 Disease denotes COVID-19 MESH:C000657245
1635 63286-63289 Gene denotes CD4 Gene:920
1636 63292-63295 Gene denotes CD8 Gene:925
1637 62991-62999 Species denotes patients Tax:9606
1638 63176-63183 Species denotes patient Tax:9606
1639 63197-63202 Species denotes woman Tax:9606
1640 63497-63505 Species denotes patients Tax:9606
1641 62706-62726 Disease denotes SARS-CoV-2 infection MESH:C000657245
1642 63012-63033 Disease denotes mild disease symptoms MESH:D009202
1643 63361-63370 Disease denotes infection MESH:D007239
1657 63883-63886 Gene denotes CD4 Gene:920
1658 63930-63933 Gene denotes TH1 Gene:51497
1659 63631-63641 Species denotes SARS-CoV-2 Tax:2697049
1660 63708-63716 Species denotes patients Tax:9606
1661 63786-63794 Species denotes patients Tax:9606
1662 63838-63848 Species denotes SARS-CoV-2 Tax:2697049
1663 64226-64234 Species denotes patients Tax:9606
1664 64072-64080 Disease denotes infected MESH:D007239
1665 64211-64225 Disease denotes critically ill MESH:D016638
1683 64386-64389 Gene denotes CD4 Gene:920
1684 64644-64647 Gene denotes CD4 Gene:920
1685 64785-64788 Gene denotes CD4 Gene:920
1686 64803-64806 Gene denotes CD8 Gene:925
1687 65014-65018 Gene denotes ORF8 Gene:43740577
1688 65079-65084 Gene denotes ORF3a Gene:43740569
1689 64319-64327 Species denotes patients Tax:9606
1690 64451-64459 Species denotes patients Tax:9606
1691 64558-64568 Species denotes SARS-CoV-2 Tax:2697049
1692 64765-64775 Species denotes SARS-CoV-2 Tax:2697049
1693 64838-64846 Species denotes patients Tax:9606
1694 65192-65202 Species denotes SARS-CoV-2 Tax:2697049
1695 65214-65222 Species denotes patients Tax:9606
1696 64310-64318 Disease denotes COVID-19 MESH:C000657245
1697 64442-64450 Disease denotes COVID-19 MESH:C000657245
1698 64701-64723 Disease denotes coronavirus infections MESH:D018352
1699 65296-65312 Disease denotes viral infections MESH:D001102
1715 65441-65444 Gene denotes CD8 Gene:925
1716 65737-65742 Gene denotes ORF3a Gene:43740569
1717 65753-65756 Gene denotes CD8 Gene:925
1718 65892-65895 Gene denotes CD8 Gene:925
1719 65405-65415 Species denotes SARS-CoV-2 Tax:2697049
1720 65556-65566 Species denotes SARS-CoV-2 Tax:2697049
1721 65626-65634 Species denotes patients Tax:9606
1722 65850-65857 Species denotes patient Tax:9606
1723 66172-66180 Species denotes patients Tax:9606
1724 66261-66269 Species denotes patients Tax:9606
1725 65457-65465 Disease denotes COVID-19 MESH:C000657245
1726 65643-65664 Disease denotes mild disease symptoms MESH:D009202
1727 66157-66171 Disease denotes critically ill MESH:D016638
1728 66252-66260 Disease denotes COVID-19 MESH:C000657245
1729 66282-66303 Disease denotes mild disease symptoms MESH:D009202
1735 67131-67134 Gene denotes CD4 Gene:920
1736 67140-67143 Gene denotes CD8 Gene:925
1737 67050-67058 Species denotes patients Tax:9606
1738 67041-67049 Disease denotes COVID-19 MESH:C000657245
1739 67271-67280 Disease denotes infection MESH:D007239
1748 67532-67537 Species denotes human Tax:9606
1749 67548-67552 Species denotes CoVs Tax:11118
1750 67590-67598 Species denotes SARS-CoV Tax:694009
1751 67985-67993 Species denotes patients Tax:9606
1752 68033-68041 Species denotes patients Tax:9606
1753 68669-68677 Species denotes patients Tax:9606
1754 67976-67984 Disease denotes COVID-19 MESH:C000657245
1755 68649-68668 Disease denotes SARS-CoV-2 infected MESH:C000657245
1764 69104-69112 Species denotes patients Tax:9606
1765 70063-70071 Species denotes patients Tax:9606
1766 70167-70175 Species denotes patients Tax:9606
1767 69095-69103 Disease denotes COVID-19 MESH:C000657245
1768 69646-69654 Disease denotes COVID-19 MESH:C000657245
1769 70152-70166 Disease denotes critically ill MESH:D016638
1770 70234-70249 Disease denotes lymphocytopenia MESH:D008231
1771 70360-70368 Disease denotes COVID-19 MESH:C000657245
1779 70560-70565 Gene denotes CD200 Gene:4345
1780 70687-70692 Gene denotes IFN-γ Gene:3458
1781 70975-70978 Gene denotes CD4 Gene:920
1782 70423-70431 Disease denotes infected MESH:D007239
1783 70473-70487 Disease denotes Virus infected MESH:D001102
1784 70719-70727 Disease denotes infected MESH:D007239
1785 71050-71058 Disease denotes infected MESH:D007239
1798 72125-72128 Gene denotes CD4 Gene:920
1799 72134-72137 Gene denotes CD8 Gene:925
1800 72648-72651 Gene denotes CD8 Gene:925
1801 72639-72642 Gene denotes CD4 Gene:920
1802 72523-72526 Gene denotes CD8 Gene:925
1803 72514-72517 Gene denotes CD4 Gene:920
1804 71596-71604 Species denotes patients Tax:9606
1805 72387-72395 Species denotes Patients Tax:9606
1806 73169-73177 Species denotes patients Tax:9606
1807 73125-73135 Species denotes SARS-CoV-2 Tax:2697049
1808 71587-71595 Disease denotes COVID-19 MESH:C000657245
1809 72378-72386 Disease denotes COVID-19 MESH:C000657245
1815 73250-73258 Species denotes patients Tax:9606
1816 73458-73466 Species denotes patients Tax:9606
1817 73477-73485 Species denotes patients Tax:9606
1818 73680-73688 Species denotes patients Tax:9606
1819 73317-73327 Species denotes SARS-CoV-2 Tax:2697049
1828 74020-74028 Species denotes patients Tax:9606
1829 74137-74145 Species denotes patients Tax:9606
1830 74326-74334 Species denotes patients Tax:9606
1831 74531-74539 Species denotes patients Tax:9606
1832 74011-74019 Disease denotes COVID-19 MESH:C000657245
1833 74522-74530 Disease denotes COVID-19 MESH:C000657245
1834 74600-74618 Disease denotes hyper-inflammation MESH:D007249
1835 74899-74907 Disease denotes COVID-19 MESH:C000657245
1837 74963-74971 Disease denotes COVID-19 MESH:C000657245
1845 75432-75435 Gene denotes TH1 Gene:51497
1846 75460-75465 Gene denotes IFN-γ Gene:3458
1847 75467-75471 Gene denotes IL-2 Gene:3558
1848 75502-75507 Gene denotes IL-17 Gene:3605
1849 75370-75378 Species denotes patients Tax:9606
1850 75571-75579 Species denotes patients Tax:9606
1851 75152-75160 Disease denotes COVID-19 MESH:C000657245
1879 75881-75886 Gene denotes IFN-γ Gene:3458
1880 75888-75894 Gene denotes GM-CSF Gene:1437
1881 75900-75904 Gene denotes IL-6 Gene:3569
1882 76121-76124 Gene denotes TH1 Gene:51497
1883 76276-76279 Gene denotes CD8 Gene:925
1884 76431-76437 Gene denotes GM-CSF Gene:1437
1885 76451-76454 Gene denotes CD8 Gene:925
1886 76532-76536 Gene denotes IL-6 Gene:3569
1887 76541-76546 Gene denotes TNF-α Gene:7124
1888 76652-76656 Gene denotes CCL2 Gene:6347
1889 76658-76664 Gene denotes CXCL10 Gene:3627
1890 76666-76673 Gene denotes Eotaxin Gene:6356
1891 76679-76685 Gene denotes IL-1RA Gene:3557
1892 76706-76709 Gene denotes CD8 Gene:925
1893 76755-76760 Gene denotes IFN-γ Gene:3458
1894 76920-76923 Gene denotes CD8 Gene:925
1895 76903-76906 Gene denotes TH1 Gene:51497
1896 75835-75838 Gene denotes TH1 Gene:51497
1897 76087-76095 Species denotes patients Tax:9606
1898 76329-76337 Species denotes patients Tax:9606
1899 76473-76481 Species denotes patients Tax:9606
1900 76583-76591 Species denotes patients Tax:9606
1901 76945-76953 Species denotes patients Tax:9606
1902 76078-76086 Disease denotes COVID-19 MESH:C000657245
1903 76320-76328 Disease denotes COVID-19 MESH:C000657245
1904 76574-76582 Disease denotes COVID-19 MESH:C000657245
1905 76936-76944 Disease denotes COVID-19 MESH:C000657245
1919 77133-77138 Gene denotes IFN-γ Gene:3458
1920 77140-77144 Gene denotes IL-2 Gene:3558
1921 77150-77155 Gene denotes TNF-α Gene:7124
1922 77159-77162 Gene denotes CD4 Gene:920
1923 77224-77228 Gene denotes IL-2 Gene:3558
1924 77230-77233 Gene denotes CD8 Gene:925
1925 77239-77244 Gene denotes IFN-γ Gene:3458
1926 77246-77249 Gene denotes CD8 Gene:925
1927 77397-77400 Gene denotes CD4 Gene:920
1928 77406-77409 Gene denotes CD8 Gene:925
1929 77052-77060 Disease denotes COVID-19 MESH:C000657245
1930 77554-77569 Disease denotes Lymphocytopenia MESH:D008231
1931 77577-77585 Disease denotes COVID-19 MESH:C000657245
1939 77646-77650 Gene denotes IL-4 Gene:3565
1940 77655-77659 Gene denotes IL-5 Gene:3567
1941 77678-77683 Gene denotes IL-17 Gene:3605
1942 78206-78214 Species denotes patients Tax:9606
1943 77921-77932 Species denotes respiratory Tax:12814
1944 77612-77615 Gene denotes TH1 Gene:51497
1945 78106-78114 Disease denotes COVID-19 MESH:C000657245
1948 78376-78384 Disease denotes COVID-19 MESH:C000657245
1949 78385-78394 Disease denotes Infection MESH:D007239
1955 78662-78670 Species denotes patients Tax:9606
1956 78565-78580 Disease denotes lymphocytopenia MESH:D008231
1957 78653-78661 Disease denotes COVID-19 MESH:C000657245
1958 78909-78917 Disease denotes COVID-19 MESH:C000657245
1959 79116-79126 Disease denotes infections MESH:D007239
1970 79216-79219 Gene denotes CD4 Gene:920
1971 79225-79228 Gene denotes CD8 Gene:925
1972 79642-79645 Gene denotes CD4 Gene:920
1973 79651-79654 Gene denotes CD8 Gene:925
1974 79832-79835 Gene denotes CD8 Gene:925
1975 79878-79888 Gene denotes granzyme B Gene:3002
1976 79163-79170 Species denotes patient Tax:9606
1977 79355-79362 Species denotes patient Tax:9606
1978 79470-79478 Species denotes patients Tax:9606
1979 79461-79469 Disease denotes COVID-19 MESH:C000657245
1982 79957-79960 Gene denotes CD4 Gene:920
1983 79966-79969 Gene denotes CD8 Gene:925
2001 80663-80666 Gene denotes CD4 Gene:920
2002 80674-80677 Gene denotes CD8 Gene:925
2003 80726-80731 Gene denotes IFN-γ Gene:3458
2004 80733-80738 Gene denotes TNF-α Gene:7124
2005 80740-80745 Gene denotes IL-17 Gene:3605
2006 80751-80755 Gene denotes IL-2 Gene:3558
2007 81029-81032 Gene denotes CD8 Gene:925
2008 81044-81047 Gene denotes CD4 Gene:920
2009 81128-81131 Gene denotes CD8 Gene:925
2010 81270-81273 Gene denotes CD8 Gene:925
2011 81337-81347 Gene denotes granzyme B Gene:3002
2012 80573-80576 Gene denotes CD8 Gene:925
2013 80564-80567 Gene denotes CD4 Gene:920
2014 80509-80517 Species denotes patients Tax:9606
2015 80921-80929 Species denotes patients Tax:9606
2016 81094-81102 Species denotes patients Tax:9606
2017 80500-80508 Disease denotes COVID-19 MESH:C000657245
2021 81744-81747 Gene denotes CD4 Gene:920
2022 81753-81756 Gene denotes CD8 Gene:925
2023 81688-81696 Species denotes patients Tax:9606
2034 82297-82300 Gene denotes CD8 Gene:925
2035 82356-82361 Gene denotes NKG2A Gene:3821
2036 82396-82401 Gene denotes IFN-γ Gene:3458
2037 82403-82407 Gene denotes IL-2 Gene:3558
2038 82413-82423 Gene denotes granzyme B Gene:3002
2039 82793-82796 Gene denotes CD8 Gene:925
2040 82819-82822 Gene denotes CD4 Gene:404704
2041 82269-82277 Species denotes patients Tax:9606
2042 82970-82978 Species denotes patients Tax:9606
2043 82260-82268 Disease denotes COVID-19 MESH:C000657245
2062 83213-83216 Gene denotes CD4 Gene:920
2063 83306-83311 Gene denotes IFN-γ Gene:3458
2064 83316-83320 Gene denotes IL-2 Gene:3558
2065 83332-83335 Gene denotes CD4 Gene:920
2066 83352-83356 Gene denotes IL-2 Gene:3558
2067 83368-83371 Gene denotes CD4 Gene:920
2068 83455-83458 Gene denotes CD8 Gene:925
2069 83519-83525 Gene denotes CTLA-4 Gene:1493
2070 83653-83656 Gene denotes CD4 Gene:920
2071 83662-83665 Gene denotes CD8 Gene:925
2072 83801-83806 Gene denotes Tim-3 Gene:84868
2073 83848-83851 Gene denotes CD8 Gene:925
2074 83858-83861 Gene denotes CD4 Gene:920
2075 83696-83704 Species denotes patients Tax:9606
2076 84205-84213 Species denotes patients Tax:9606
2077 83970-83973 Gene denotes CD4 Gene:920
2078 83979-83982 Gene denotes CD8 Gene:925
2079 83556-83560 Disease denotes TGIT
2095 84532-84535 Gene denotes CD4 Gene:920
2096 84541-84544 Gene denotes CD8 Gene:925
2097 84767-84770 Gene denotes CD8 Gene:925
2098 84856-84859 Gene denotes CD8 Gene:925
2099 85006-85009 Gene denotes CD4 Gene:920
2100 85015-85018 Gene denotes CD8 Gene:925
2101 85110-85113 Gene denotes CD8 Gene:925
2102 85143-85147 Gene denotes GZMA Gene:3001
2103 85152-85156 Gene denotes GZMK Gene:3003
2104 84355-84363 Species denotes patients Tax:9606
2105 84973-84981 Species denotes patients Tax:9606
2106 84346-84354 Disease denotes COVID-19 MESH:C000657245
2107 84423-84432 Disease denotes infection MESH:D007239
2108 84964-84972 Disease denotes COVID-19 MESH:C000657245
2109 85347-85356 Disease denotes infection MESH:D007239
2130 85474-85477 Gene denotes CD4 Gene:920
2131 85483-85486 Gene denotes CD8 Gene:925
2132 85692-85695 Gene denotes CD4 Gene:920
2133 85750-85755 Gene denotes IFN-γ Gene:3458
2134 85757-85761 Gene denotes IL-2 Gene:3558
2135 85770-85774 Gene denotes IL-6 Gene:3569
2136 85780-85786 Gene denotes GM-CSF Gene:1437
2137 85806-85809 Gene denotes CD8 Gene:925
2138 85889-85894 Gene denotes IFN-γ Gene:3458
2139 85982-86002 Gene denotes granzyme A, B, and K Gene:3001
2140 86011-86016 Gene denotes GZM-A Gene:3001
2141 86208-86212 Gene denotes Tim3 Gene:84868
2142 86218-86223 Gene denotes NKG2A Gene:3821
2143 86736-86740 Gene denotes IL4R Gene:3566
2144 86742-86750 Gene denotes TNFSF13B Gene:10673
2145 86756-86760 Gene denotes XBP1 Gene:7494
2146 85935-85938 Gene denotes CD8 Gene:925
2147 85423-85443 Disease denotes SARS-CoV-2 infection MESH:C000657245
2148 85602-85611 Disease denotes infection MESH:D007239
2149 85903-85923 Disease denotes SARS-CoV-2 infection MESH:C000657245
2163 86976-86979 Gene denotes CD4 Gene:920
2164 87015-87018 Gene denotes CD8 Gene:925
2165 87165-87168 Gene denotes CD8 Gene:925
2166 87418-87421 Gene denotes CD8 Gene:925
2167 87820-87823 Gene denotes CD4 Gene:920
2168 88000-88003 Gene denotes CD8 Gene:925
2169 87508-87511 Gene denotes CD8 Gene:925
2170 87201-87209 Species denotes patients Tax:9606
2171 87398-87408 Species denotes SARS-CoV-2 Tax:2697049
2172 87570-87578 Species denotes patients Tax:9606
2173 87377-87386 Species denotes Influenza Tax:11320
2174 87561-87569 Disease denotes COVID-19 MESH:C000657245
2175 88036-88045 Disease denotes infection MESH:D007239
2184 88159-88162 Gene denotes CD4 Gene:920
2185 88168-88171 Gene denotes CD8 Gene:925
2186 88256-88259 Gene denotes CD4 Gene:920
2187 88296-88299 Gene denotes CD4 Gene:920
2188 88307-88312 Gene denotes CD127 Gene:3575
2189 88392-88395 Gene denotes CD8 Gene:925
2190 88423-88426 Gene denotes CD8 Gene:925
2191 88672-88680 Species denotes patients Tax:9606
2193 88715-88723 Disease denotes COVID-19 MESH:C000657245
2197 88823-88827 Species denotes CoVs Tax:11118
2198 89021-89029 Species denotes patients Tax:9606
2199 89012-89020 Disease denotes COVID-19 MESH:C000657245
2209 90996-91001 Gene denotes CD138 Gene:6382
2210 89642-89650 Species denotes patients Tax:9606
2211 90348-90356 Species denotes patients Tax:9606
2212 90758-90766 Species denotes patients Tax:9606
2213 90444-90454 Species denotes SARS-CoV-2 Tax:2697049
2214 90841-90851 Species denotes SARS-CoV-2 Tax:2697049
2215 89314-89322 Disease denotes COVID-19 MESH:C000657245
2216 90333-90347 Disease denotes critically ill MESH:D016638
2217 90578-90592 Disease denotes critically ill MESH:D016638
2236 91615-91620 Gene denotes Bcl-6 Gene:604
2237 91622-91644 Gene denotes germinal center (GC) B Gene:2629
2238 91918-91923 Gene denotes TNF-α Gene:7124
2239 91990-91995 Gene denotes TNF-α Gene:7124
2240 91847-91850 Gene denotes TH1 Gene:51497
2241 91675-91683 Species denotes patients Tax:9606
2242 92321-92329 Species denotes patients Tax:9606
2243 92401-92409 Species denotes patients Tax:9606
2244 92613-92621 Species denotes patients Tax:9606
2245 92645-92653 Species denotes patients Tax:9606
2246 92828-92836 Species denotes patients Tax:9606
2247 93118-93126 Species denotes patients Tax:9606
2248 91466-91474 Disease denotes COVID-19 MESH:C000657245
2249 91705-91713 Disease denotes COVID-19 MESH:C000657245
2250 92106-92114 Disease denotes COVID-19 MESH:C000657245
2251 92312-92320 Disease denotes COVID-19 MESH:C000657245
2252 92748-92756 Disease denotes Covid-19 MESH:C000657245
2253 93109-93117 Disease denotes COVID-19 MESH:C000657245
2255 93238-93246 Disease denotes COVID-19 MESH:C000657245
2263 94065-94073 Species denotes patients Tax:9606
2264 94423-94431 Species denotes patients Tax:9606
2265 94726-94734 Species denotes patients Tax:9606
2266 93322-93330 Disease denotes COVID-19 MESH:C000657245
2267 93467-93475 Disease denotes COVID-19 MESH:C000657245
2268 93524-93540 Disease denotes viral infections MESH:D001102
2269 93588-93607 Disease denotes SARS-CoV infections MESH:C000657245
2274 95080-95084 Gene denotes IL-6 Gene:3569
2275 95086-95092 Gene denotes CXCL10 Gene:3627
2276 95126-95129 Gene denotes C5a Gene:728
2277 95351-95361 Species denotes SARS-CoV-2 Tax:2697049
2286 95679-95687 Species denotes patients Tax:9606
2287 95737-95745 Species denotes patients Tax:9606
2288 95914-95922 Species denotes patients Tax:9606
2289 96331-96339 Species denotes patients Tax:9606
2290 96378-96385 Species denotes persons Tax:9606
2291 96686-96694 Species denotes patients Tax:9606
2292 96986-96994 Species denotes patients Tax:9606
2293 95670-95678 Disease denotes COVID-19 MESH:C000657245
2307 97239-97247 Species denotes patients Tax:9606
2308 97308-97316 Species denotes patients Tax:9606
2309 97371-97379 Species denotes patients Tax:9606
2310 97491-97499 Species denotes patients Tax:9606
2311 97545-97553 Species denotes patients Tax:9606
2312 97730-97744 Species denotes rhesus monkeys Tax:9544
2313 97778-97786 Species denotes SARS-CoV Tax:694009
2314 97135-97153 Disease denotes SARS-CoV infection MESH:C000657245
2315 97221-97238 Disease denotes SARS-CoV infected MESH:C000657245
2316 97760-97768 Disease denotes infected MESH:D007239
2317 97860-97869 Disease denotes infection MESH:D007239
2318 98096-98113 Disease denotes acute lung injury MESH:D055371
2319 98237-98248 Disease denotes lung injury MESH:D055370
2333 99854-99855 Gene denotes N Gene:43740575
2334 99701-99702 Gene denotes N Gene:43740575
2335 98875-98880 Species denotes woman Tax:9606
2336 99034-99042 Species denotes patients Tax:9606
2337 99172-99180 Species denotes patients Tax:9606
2338 99387-99395 Species denotes patients Tax:9606
2339 99594-99602 Species denotes patients Tax:9606
2340 100029-100037 Species denotes patients Tax:9606
2341 100239-100252 Species denotes coronaviruses Tax:11118
2342 99670-99680 Species denotes SARS-CoV-2 Tax:2697049
2343 99378-99386 Disease denotes COVID-19 MESH:C000657245
2344 100020-100028 Disease denotes COVID-19 MESH:C000657245
2345 100406-100414 Disease denotes COVID-19 MESH:C000657245
2354 100626-100631 Gene denotes TNF-α Gene:7124
2355 100587-100595 Species denotes patients Tax:9606
2356 100740-100748 Species denotes patients Tax:9606
2357 100927-100935 Species denotes patients Tax:9606
2358 100942-100949 Species denotes patient Tax:9606
2359 101286-101293 Species denotes patient Tax:9606
2360 101498-101506 Species denotes patients Tax:9606
2361 100912-100926 Disease denotes critically ill MESH:D016638
2363 101531-101541 Species denotes SARS-CoV-2 Tax:2697049
2377 102033-102034 Gene denotes N Gene:43740575
2378 101796-101804 Species denotes SARS-CoV Tax:694009
2379 101862-101872 Species denotes SARS-CoV-2 Tax:2697049
2380 101944-101952 Species denotes patients Tax:9606
2381 101989-101997 Species denotes SARS-CoV Tax:694009
2382 102027-102032 Species denotes CoV-2 Tax:2697049
2383 102058-102066 Species denotes patients Tax:9606
2384 102139-102149 Species denotes SARS-CoV-2 Tax:2697049
2385 102275-102288 Species denotes coronaviruses Tax:11118
2386 101607-101615 Species denotes SARS-CoV Tax:694009
2387 101669-101679 Species denotes SARS-CoV-2 Tax:2697049
2388 101813-101819 Chemical denotes CR3022
2389 101824-101828 Chemical denotes S309
2399 102589-102599 Species denotes SARS-CoV-2 Tax:2697049
2400 102606-102614 Species denotes SARS-CoV Tax:694009
2401 102615-102623 Species denotes patients Tax:9606
2402 102822-102832 Species denotes SARS-CoV-2 Tax:2697049
2403 102837-102845 Species denotes SARS-CoV Tax:694009
2404 102913-102923 Species denotes SARS-CoV-2 Tax:2697049
2405 103105-103115 Species denotes SARS-CoV-2 Tax:2697049
2406 103148-103152 Species denotes CoVs Tax:11118
2407 102959-102965 Chemical denotes CR3022
2413 103643-103651 Species denotes patients Tax:9606
2414 103878-103888 Species denotes SARS-CoV-2 Tax:2697049
2415 104138-104148 Species denotes SARS-CoV-2 Tax:2697049
2416 103778-103785 Chemical denotes BD-368-
2417 103634-103642 Disease denotes COVID-19 MESH:C000657245
2419 104342-104350 Disease denotes COVID-19 MESH:C000657245
2428 104611-104632 Gene denotes Fc gamma receptor IIa Gene:2212
2429 104634-104641 Gene denotes FcγRIIa Gene:2212
2430 105017-105025 Species denotes patients Tax:9606
2431 105176-105184 Species denotes SARS-CoV Tax:694009
2432 105302-105310 Species denotes SARS-CoV Tax:694009
2433 105314-105324 Species denotes SARS-CoV-2 Tax:2697049
2434 105427-105431 Species denotes CoVs Tax:11118
2435 105438-105446 Species denotes patients Tax:9606
2437 105586-105594 Disease denotes COVID-19 MESH:C000657245
2445 105650-105658 Species denotes patients Tax:9606
2446 106376-106382 Species denotes meagre Tax:172269
2447 105641-105649 Disease denotes COVID-19 MESH:C000657245
2448 105720-105729 Disease denotes infection MESH:D007239
2449 105989-105997 Disease denotes COVID-19 MESH:C000657245
2450 106101-106110 Disease denotes infection MESH:D007239
2451 106228-106250 Disease denotes eosinophilic pneumonia MESH:D011657
2462 107390-107395 Gene denotes IL-18 Gene:3606
2463 106607-106615 Species denotes patients Tax:9606
2464 106837-106845 Species denotes patients Tax:9606
2465 106996-107004 Species denotes patients Tax:9606
2466 107251-107259 Species denotes patients Tax:9606
2467 106598-106606 Disease denotes COVID-19 MESH:C000657245
2468 106987-106995 Disease denotes COVID-19 MESH:C000657245
2469 107236-107250 Disease denotes critically ill MESH:D016638
2470 107511-107520 Disease denotes infection MESH:D007239
2471 107877-107885 Disease denotes COVID-19 MESH:C000657245
2474 107917-107932 Disease denotes Lymphocytopenia MESH:D008231
2475 107940-107948 Disease denotes COVID-19 MESH:C000657245
2487 108065-108073 Species denotes patients Tax:9606
2488 108563-108573 Species denotes SARS-CoV-2 Tax:2697049
2489 108010-108025 Disease denotes lymphocytopenia MESH:D008231
2490 108041-108055 Disease denotes critically ill MESH:D016638
2491 108056-108064 Disease denotes COVID-19 MESH:C000657245
2492 108384-108399 Disease denotes lymphocytopenia MESH:D008231
2493 108440-108448 Disease denotes COVID-19 MESH:C000657245
2494 108540-108555 Disease denotes lymphocytopenia MESH:D008231
2495 108691-108707 Disease denotes viral infections MESH:D001102
2496 108932-108941 Disease denotes infection MESH:D007239
2497 108978-108986 Disease denotes necrosis MESH:D009336
2509 109266-109269 Gene denotes CD8 Gene:925
2510 109675-109680 Gene denotes CD11a Gene:3683
2511 109738-109741 Gene denotes CD4 Gene:920
2512 109747-109750 Gene denotes CD8 Gene:925
2513 109066-109074 Species denotes patients Tax:9606
2514 109328-109336 Species denotes patients Tax:9606
2515 109635-109643 Species denotes patients Tax:9606
2516 109057-109065 Disease denotes COVID-19 MESH:C000657245
2517 109482-109497 Disease denotes lymphocytopenia MESH:D008231
2518 109626-109634 Disease denotes COVID-19 MESH:C000657245
2519 109890-109898 Disease denotes infected MESH:D007239
2528 110333-110336 Gene denotes CD4 Gene:920
2529 110342-110345 Gene denotes CD8 Gene:925
2530 110463-110466 Gene denotes CD8 Gene:925
2531 110297-110304 Species denotes patient Tax:9606
2532 109971-109986 Disease denotes lymphocytopenia MESH:D008231
2533 110180-110189 Disease denotes infection MESH:D007239
2534 110702-110711 Disease denotes infection MESH:D007239
2535 110742-110757 Disease denotes lymphocytopenia MESH:D008231
2561 111592-111595 Gene denotes CD4 Gene:920
2562 111682-111686 Gene denotes IL-2 Gene:3558
2563 111688-111693 Gene denotes IL-10 Gene:3586
2564 111695-111700 Gene denotes IL-21 Gene:59067
2565 111702-111707 Gene denotes IFN-γ Gene:3458
2566 111712-111717 Gene denotes TNF-α Gene:7124
2567 111789-111795 Gene denotes CTLA-4 Gene:1493
2568 111797-111802 Gene denotes LAG-3 Gene:3902
2569 111804-111809 Gene denotes CD244 Gene:51744
2570 111821-111826 Gene denotes TIM-3 Gene:84868
2571 111879-111882 Gene denotes CD8 Gene:925
2572 111941-111945 Gene denotes IL-2 Gene:3558
2573 111947-111952 Gene denotes IFN-γ Gene:3458
2574 111954-111959 Gene denotes TNF-α Gene:7124
2575 112047-112052 Gene denotes CD122 Gene:3560
2576 112120-112126 Gene denotes CTLA-4 Gene:1493
2577 112128-112133 Gene denotes NKG2A Gene:3821
2578 112135-112140 Gene denotes TIGIT Gene:201633
2579 112142-112147 Gene denotes LAG-3 Gene:3902
2580 112149-112154 Gene denotes CD244 Gene:51744
2581 112166-112171 Gene denotes CD160 Gene:11126
2582 112374-112380 Gene denotes LAIR-1 Gene:3903
2583 112057-112062 Gene denotes CD127 Gene:3575
2584 110937-110945 Species denotes patients Tax:9606
2585 110928-110936 Disease denotes COVID-19 MESH:C000657245
2604 112531-112534 Gene denotes CD8 Gene:925
2605 112542-112545 Gene denotes CD4 Gene:920
2606 112863-112867 Gene denotes BATF Gene:10538
2607 112869-112873 Gene denotes IRF4 Gene:3662
2608 112879-112884 Gene denotes CD274 Gene:29126
2609 113716-113719 Gene denotes CD8 Gene:925
2610 112591-112599 Species denotes patients Tax:9606
2611 113118-113126 Species denotes patients Tax:9606
2612 113369-113377 Species denotes patients Tax:9606
2613 113709-113713 Species denotes LCMV Tax:11623
2614 112582-112590 Disease denotes COVID-19 MESH:C000657245
2615 113090-113105 Disease denotes lymphocytopenia MESH:D008231
2616 113109-113117 Disease denotes COVID-19 MESH:C000657245
2617 113199-113208 Disease denotes infection MESH:D007239
2618 113234-113249 Disease denotes viral infection MESH:D001102
2619 113354-113368 Disease denotes critically ill MESH:D016638
2620 113581-113597 Disease denotes viral infections MESH:D001102
2621 113660-113669 Disease denotes infection MESH:D007239
2637 113852-113855 Gene denotes CD8 Gene:925
2638 114007-114010 Gene denotes CD8 Gene:925
2639 114597-114602 Gene denotes IL-10 Gene:3586
2640 114607-114612 Gene denotes TGF-β Gene:7039
2641 114616-114619 Gene denotes CD8 Gene:925
2642 114773-114776 Gene denotes CD8 Gene:925
2643 114723-114731 Species denotes patients Tax:9606
2644 114860-114868 Species denotes patients Tax:9606
2645 114882-114893 Chemical denotes lactic acid MESH:D019344
2646 113841-113850 Disease denotes infection MESH:D007239
2647 114068-114106 Disease denotes immunodeficiency virus (HIV) infection MESH:D015658
2648 114350-114359 Disease denotes infection MESH:D007239
2649 114463-114478 Disease denotes viral infection MESH:D001102
2650 114714-114722 Disease denotes COVID-19 MESH:C000657245
2651 114851-114859 Disease denotes COVID-19 MESH:C000657245
2665 115122-115125 Gene denotes CD4 Gene:920
2666 115470-115485 Species denotes influenza virus Tax:11308
2667 115487-115491 Species denotes H5N1 Tax:102793
2668 115880-115888 Species denotes SARS-CoV Tax:694009
2669 115999-116009 Species denotes SARS-CoV-2 Tax:2697049
2670 115236-115247 Species denotes respiratory Tax:12814
2671 115086-115089 Species denotes HIV Tax:12721
2672 115017-115032 Disease denotes lymphocytopenia MESH:D008231
2673 115074-115084 Disease denotes infections MESH:D007239
2674 115457-115466 Disease denotes infection MESH:D007239
2675 115522-115531 Disease denotes infection MESH:D007239
2676 115733-115742 Disease denotes infection MESH:D007239
2677 116092-116100 Disease denotes COVID-19 MESH:C000657245
2699 116346-116351 Gene denotes HMGB1 Gene:3146
2700 117044-117052 Species denotes patients Tax:9606
2701 117644-117652 Species denotes Patients Tax:9606
2702 117862-117870 Species denotes Patients Tax:9606
2703 117968-117976 Species denotes patients Tax:9606
2704 118207-118214 Species denotes patient Tax:9606
2705 118308-118316 Species denotes patients Tax:9606
2706 116341-116344 Chemical denotes ROS
2707 116250-116265 Disease denotes lymphocytopenia MESH:D008231
2708 116400-116408 Disease denotes infected MESH:D007239
2709 116740-116755 Disease denotes lymphocytopenia MESH:D008231
2710 116821-116836 Disease denotes lymphocytopenia MESH:D008231
2711 116864-116872 Disease denotes COVID-19 MESH:C000657245
2712 117221-117229 Disease denotes COVID-19 MESH:C000657245
2713 117230-117239 Disease denotes infection MESH:D007239
2714 117276-117291 Disease denotes lymphocytopenia MESH:D008231
2715 117349-117358 Disease denotes infection MESH:D007239
2716 117542-117550 Disease denotes COVID-19 MESH:C000657245
2717 117658-117673 Disease denotes lymphocytopenia MESH:D008231
2718 118175-118183 Disease denotes COVID-19 MESH:C000657245
2719 118355-118359 Disease denotes ARDS MESH:D012128
2722 118455-118462 Species denotes patient Tax:9606
2723 118766-118774 Disease denotes COVID-19 MESH:C000657245
2725 118795-118803 Disease denotes COVID-19 MESH:C000657245
2740 119388-119392 Gene denotes IL-6 Gene:3569
2741 119394-119399 Gene denotes TNF-α Gene:7124
2742 119405-119410 Gene denotes IL1-β Gene:3552
2743 119440-119442 Gene denotes CS Gene:1431
2744 119241-119243 Gene denotes CS Gene:1431
2745 119020-119022 Gene denotes CS Gene:1431
2746 118881-118883 Gene denotes CS Gene:1431
2747 118848-118856 Species denotes patients Tax:9606
2748 119742-119750 Species denotes patients Tax:9606
2749 118824-118838 Disease denotes critically ill MESH:D016638
2750 118839-118847 Disease denotes COVID-19 MESH:C000657245
2751 119212-119223 Disease denotes lung damage MESH:D008171
2752 119306-119311 Disease denotes CAR-T MESH:D056733
2753 119712-119726 Disease denotes critically ill MESH:D016638
2785 120089-120094 Gene denotes IL-1β Gene:3552
2786 120096-120102 Gene denotes IL-1RA Gene:3557
2787 120104-120109 Gene denotes IL-17 Gene:3605
2788 120111-120115 Gene denotes IL-8 Gene:3576
2789 120117-120121 Gene denotes IL-9 Gene:3578
2790 120123-120128 Gene denotes IL-10 Gene:3586
2791 120141-120146 Gene denotes G-CSF Gene:1440
2792 120148-120154 Gene denotes GM-CSF Gene:1437
2793 120156-120161 Gene denotes IFN-γ Gene:3458
2794 120163-120169 Gene denotes CXCL10 Gene:3627
2795 120171-120175 Gene denotes CCL2 Gene:6347
2796 120177-120181 Gene denotes CCL3 Gene:6348
2797 120183-120187 Gene denotes CCL4 Gene:6351
2798 120195-120200 Gene denotes TNF-α Gene:7124
2799 120289-120294 Gene denotes IL1-β Gene:3552
2800 120296-120301 Gene denotes IFN-γ Gene:3458
2801 120307-120311 Gene denotes IL-6 Gene:3569
2802 120436-120441 Gene denotes G-CSF Gene:1440
2803 120443-120449 Gene denotes CXCL10 Gene:3627
2804 120451-120455 Gene denotes CCL2 Gene:6347
2805 120457-120461 Gene denotes CCL3 Gene:6348
2806 120467-120472 Gene denotes TNF-α Gene:7124
2807 120324-120327 Gene denotes TH1 Gene:51497
2808 119969-119977 Species denotes patients Tax:9606
2809 120234-120242 Species denotes patients Tax:9606
2810 120376-120384 Species denotes SARS-CoV Tax:694009
2811 120713-120721 Species denotes patients Tax:9606
2812 120901-120912 Species denotes respiratory Tax:12814
2813 119960-119968 Disease denotes COVID-19 MESH:C000657245
2814 120704-120712 Disease denotes COVID-19 MESH:C000657245
2815 121022-121030 Disease denotes COVID-19 MESH:C000657245
2837 121145-121149 Gene denotes IL-2 Gene:3558
2838 121151-121155 Gene denotes IL-6 Gene:3569
2839 121157-121162 Gene denotes IL-10 Gene:3586
2840 121167-121172 Gene denotes IFN-γ Gene:3458
2841 121247-121251 Gene denotes IL-6 Gene:3569
2842 121253-121258 Gene denotes IL-10 Gene:3586
2843 121694-121699 Gene denotes IL-2R Gene:3559
2844 121701-121705 Gene denotes IL-6 Gene:3569
2845 121707-121711 Gene denotes IL-8 Gene:3576
2846 121713-121718 Gene denotes IL-10 Gene:3586
2847 121720-121725 Gene denotes TNF-α Gene:7124
2848 121870-121875 Gene denotes IL-1β Gene:3552
2849 121405-121413 Species denotes patients Tax:9606
2850 121729-121737 Species denotes patients Tax:9606
2851 121932-121940 Species denotes patients Tax:9606
2852 122067-122075 Species denotes patients Tax:9606
2853 122115-122123 Species denotes patients Tax:9606
2854 121444-121452 Disease denotes diabetes MESH:D003920
2855 121454-121466 Disease denotes hypertension MESH:D006973
2856 121468-121484 Disease denotes fungal infection MESH:D009181
2857 122029-122043 Disease denotes critically ill MESH:D016638
2889 122351-122356 Gene denotes IL-10 Gene:3586
2890 122358-122362 Gene denotes CCL2 Gene:6347
2891 122364-122370 Gene denotes CXCL10 Gene:3627
2892 122372-122376 Gene denotes CCL3 Gene:6348
2893 122382-122386 Gene denotes CCL4 Gene:6351
2894 122495-122500 Gene denotes IL-1β Gene:3552
2895 122502-122506 Gene denotes IL-2 Gene:3558
2896 122508-122512 Gene denotes IL-4 Gene:3565
2897 122514-122518 Gene denotes IL-5 Gene:3567
2898 122520-122524 Gene denotes IL-6 Gene:3569
2899 122526-122530 Gene denotes IL-8 Gene:3576
2900 122532-122537 Gene denotes IL-10 Gene:3586
2901 122549-122554 Gene denotes IL-17 Gene:3605
2902 122556-122561 Gene denotes IFN-α Gene:3439
2903 122563-122568 Gene denotes IFN-γ Gene:3458
2904 122574-122579 Gene denotes TNF-α Gene:7124
2905 122659-122664 Gene denotes IL-1β Gene:3552
2906 122666-122670 Gene denotes IL-6 Gene:3569
2907 122676-122680 Gene denotes IL-8 Gene:3576
2908 122952-122957 Gene denotes IL1RN Gene:3557
2909 122959-122963 Gene denotes IL1β Gene:3552
2910 122965-122971 Gene denotes CXCL17 Gene:284340
2911 122973-122978 Gene denotes CXCL8 Gene:3576
2912 122980-122985 Gene denotes CXCL1 Gene:2919
2913 122987-122992 Gene denotes CXCL2 Gene:2920
2914 122994-122998 Gene denotes CCL2 Gene:6347
2915 123004-123008 Gene denotes CCL7 Gene:6354
2916 122706-122714 Species denotes patients Tax:9606
2917 122804-122812 Species denotes patients Tax:9606
2918 122691-122705 Disease denotes critically ill MESH:D016638
2919 122795-122803 Disease denotes COVID-19 MESH:C000657245
2954 123099-123104 Gene denotes CXCL9 Gene:4283
2955 123106-123112 Gene denotes CXCL10 Gene:3627
2956 123114-123120 Gene denotes CXCL11 Gene:6373
2957 123126-123132 Gene denotes CXCL16 Gene:58191
2958 123238-123243 Gene denotes IL-1β Gene:3552
2959 123245-123249 Gene denotes IL-6 Gene:3569
2960 123251-123256 Gene denotes TNF-α Gene:7124
2961 123284-123288 Gene denotes CCL2 Gene:6347
2962 123290-123294 Gene denotes CCL3 Gene:6348
2963 123296-123300 Gene denotes CCL4 Gene:6351
2964 123306-123310 Gene denotes CCL7 Gene:6354
2965 123447-123451 Gene denotes IL-6 Gene:3569
2966 123453-123458 Gene denotes TNF-a Gene:7124
2967 123463-123468 Gene denotes IL-10 Gene:3586
2968 123825-123829 Gene denotes IL-6 Gene:3569
2969 123850-123855 Gene denotes TNF-α Gene:7124
2970 124075-124079 Gene denotes IL-6 Gene:3569
2971 124280-124284 Gene denotes IL-6 Gene:3569
2972 124467-124472 Gene denotes IL-6R Gene:3570
2973 124633-124639 Gene denotes GM-CSF Gene:1437
2974 123156-123164 Species denotes patients Tax:9606
2975 123521-123529 Species denotes patients Tax:9606
2976 124331-124339 Species denotes patients Tax:9606
2977 124748-124756 Species denotes patients Tax:9606
2978 124872-124880 Species denotes patients Tax:9606
2979 124059-124067 Species denotes patients Tax:9606
2980 124482-124493 Chemical denotes tocilizumab MESH:C502936
2981 123147-123155 Disease denotes COVID-19 MESH:C000657245
2982 123695-123704 Disease denotes infection MESH:D007239
2983 124142-124150 Disease denotes COVID-19 MESH:C000657245
2984 124186-124190 Disease denotes ARDS MESH:D012128
2985 124322-124330 Disease denotes COVID-19 MESH:C000657245
2986 124739-124747 Disease denotes COVID-19 MESH:C000657245
2987 124863-124871 Disease denotes COVID-19 MESH:C000657245
2991 125036-125044 Species denotes patients Tax:9606
2992 124976-125004 Disease denotes establishing lymphocytopenia MESH:D008231
2993 125027-125035 Disease denotes COVID-19 MESH:C000657245
3384 125152-125155 Gene denotes CD8 Gene:925
3385 125161-125164 Gene denotes CD4 Gene:920
3386 125234-125238 Gene denotes IL-2 Gene:3558
3387 125240-125244 Gene denotes IL-6 Gene:3569
3388 125246-125251 Gene denotes IL-10 Gene:3586
3389 125257-125262 Gene denotes IFN-γ Gene:3458
3390 125327-125331 Gene denotes IL-4 Gene:3565
3391 125336-125341 Gene denotes TNF-α Gene:7124
3392 125664-125669 Gene denotes TNF-α Gene:7124
3393 125671-125676 Gene denotes IFN-γ Gene:3458
3394 125678-125682 Gene denotes IL-2 Gene:3558
3395 125684-125688 Gene denotes IL-4 Gene:3565
3396 125690-125694 Gene denotes IL-6 Gene:3569
3397 125699-125704 Gene denotes IL-10 Gene:3586
3398 125753-125756 Gene denotes CRP Gene:1401
3399 125860-125865 Gene denotes IL-10 Gene:3586
3400 126214-126217 Gene denotes AST Gene:26503
3401 126675-126679 Gene denotes IL-6 Gene:3569
3402 126928-126932 Gene denotes IL-2 Gene:3558
3403 126934-126938 Gene denotes IL-7 Gene:3574
3404 126940-126945 Gene denotes IL-10 Gene:3586
3405 126947-126951 Gene denotes GCSF Gene:1440
3406 126953-126958 Gene denotes IP-10 Gene:3627
3407 126960-126966 Gene denotes CXCL10 Gene:3627
3408 126969-126973 Gene denotes CCL2 Gene:6347
3409 126975-126979 Gene denotes CCL3 Gene:6348
3410 126985-126990 Gene denotes TNF-α Gene:7124
3411 127079-127083 Gene denotes IL-4 Gene:3565
3412 127137-127140 Gene denotes AST Gene:26503
3413 127333-127337 Gene denotes IL-6 Gene:3569
3414 127386-127389 Gene denotes CRP Gene:1401
3415 127503-127506 Gene denotes AST Gene:26503
3416 127683-127686 Gene denotes CD4 Gene:920
3417 127694-127697 Gene denotes CD8 Gene:925
3418 127874-127879 Gene denotes IFN-γ Gene:3458
3419 127881-127887 Gene denotes IL-1ra Gene:3557
3420 127889-127895 Gene denotes IL-2ra Gene:3559
3421 127897-127901 Gene denotes IL-6 Gene:3569
3422 127903-127908 Gene denotes IL-10 Gene:3586
3423 127910-127915 Gene denotes IL-18 Gene:3606
3424 127917-127920 Gene denotes HGF Gene:3082
3425 127922-127926 Gene denotes CCL7 Gene:6354
3426 127928-127931 Gene denotes MIG Gene:4283
3427 127933-127938 Gene denotes M-CSF Gene:1435
3428 127940-127945 Gene denotes G-CSF Gene:1440
3429 127955-127960 Gene denotes CTACK Gene:10850
3430 127966-127971 Gene denotes IP-10 Gene:3627
3431 127974-127979 Gene denotes IP-10 Gene:3627
3432 127981-127985 Gene denotes CCL7 Gene:6354
3433 127991-127997 Gene denotes IL-1RA Gene:3557
3434 128302-128305 Gene denotes CD4 Gene:920
3435 128366-128371 Gene denotes IL-2R Gene:3559
3436 128373-128377 Gene denotes IL-6 Gene:3569
3437 128379-128384 Gene denotes IL-10 Gene:3586
3438 128390-128395 Gene denotes TNF-α Gene:7124
3439 128455-128458 Gene denotes CRP Gene:1401
3440 128532-128537 Gene denotes IFN-γ Gene:3458
3441 128683-128686 Gene denotes CD4 Gene:920
3442 128694-128697 Gene denotes CD8 Gene:925
3443 129112-129115 Gene denotes CD4 Gene:920
3444 129132-129135 Gene denotes CD8 Gene:925
3445 129379-129384 Gene denotes TNF-α Gene:7124
3446 129386-129391 Gene denotes IL-2R Gene:3559
3447 129397-129401 Gene denotes IL-6 Gene:3569
3448 129403-129407 Gene denotes IL-8 Gene:3576
3449 129409-129414 Gene denotes IL-10 Gene:3586
3450 129426-129429 Gene denotes CRP Gene:1401
3451 129516-129521 Gene denotes IL-1β Gene:3552
3452 129637-129640 Gene denotes CD4 Gene:920
3453 129643-129646 Gene denotes CD8 Gene:925
3454 129798-129802 Gene denotes IL-2 Gene:3558
3455 129804-129808 Gene denotes IL-6 Gene:3569
3456 129810-129815 Gene denotes IL-10 Gene:3586
3457 129821-129826 Gene denotes TNF-α Gene:7124
3458 129867-129871 Gene denotes IL-4 Gene:3565
3459 129924-129928 Gene denotes IL-2 Gene:3558
3460 129933-129937 Gene denotes IL-6 Gene:3569
3461 130205-130208 Gene denotes CD4 Gene:920
3462 130211-130214 Gene denotes CD8 Gene:925
3463 130268-130273 Gene denotes IFN-γ Gene:3458
3464 130275-130279 Gene denotes IL-2 Gene:3558
3465 130281-130285 Gene denotes IL-6 Gene:3569
3466 130291-130296 Gene denotes IL-10 Gene:3586
3467 130363-130367 Gene denotes IL-4 Gene:3565
3468 130603-130606 Gene denotes CD4 Gene:920
3469 130617-130620 Gene denotes CD8 Gene:925
3470 130782-130785 Gene denotes CD4 Gene:920
3471 130796-130799 Gene denotes CD8 Gene:925
3472 131055-131058 Gene denotes CD4 Gene:920
3473 131109-131114 Gene denotes IFN-γ Gene:3458
3474 131120-131125 Gene denotes TNF-α Gene:7124
3475 131177-131180 Gene denotes CD8 Gene:925
3476 131251-131261 Gene denotes granzyme B Gene:3002
3477 131303-131306 Gene denotes CD8 Gene:925
3478 131360-131366 Gene denotes CTLA-4 Gene:1493
3479 131465-131469 Gene denotes IL-6 Gene:3569
3480 131474-131479 Gene denotes TNF-α Gene:7124
3481 131697-131700 Gene denotes CD8 Gene:925
3482 131781-131786 Gene denotes IFN-γ Gene:3458
3483 131788-131792 Gene denotes IL-2 Gene:3558
3484 131794-131804 Gene denotes granzyme-B Gene:3002
3485 131808-131811 Gene denotes CD8 Gene:925
3486 131832-131837 Gene denotes TNF-α Gene:7124
3487 131886-131889 Gene denotes CD8 Gene:925
3488 132154-132158 Gene denotes IL-6 Gene:3569
3489 132174-132177 Gene denotes AST Gene:26503
3490 132184-132193 Gene denotes Myoglobin Gene:4151
3491 132498-132501 Gene denotes CD4 Gene:920
3492 132507-132510 Gene denotes CD8 Gene:925
3493 132667-132671 Gene denotes TIM3 Gene:84868
3494 132729-132734 Gene denotes TNF-α Gene:7124
3495 132736-132740 Gene denotes IL-6 Gene:3569
3496 132745-132750 Gene denotes IL-10 Gene:3586
3497 132837-132842 Gene denotes IFN-γ Gene:3458
3498 132844-132848 Gene denotes IL-2 Gene:3558
3499 132854-132858 Gene denotes IL-4 Gene:3565
3500 132925-132930 Gene denotes IFN-γ Gene:3458
3501 132932-132937 Gene denotes IL-10 Gene:3586
3502 132939-132943 Gene denotes IL-6 Gene:3569
3503 132949-132954 Gene denotes TNF-α Gene:7124
3504 133540-133545 Gene denotes IL-10 Gene:3586
3505 133547-133550 Gene denotes IL6 Gene:3569
3506 133556-133561 Gene denotes TNF-α Gene:7124
3507 133669-133672 Gene denotes CRP Gene:1401
3508 133684-133688 Gene denotes IL-6 Gene:3569
3509 133758-133762 Gene denotes IL-6 Gene:3569
3510 133999-134002 Gene denotes CD4 Gene:920
3511 134008-134011 Gene denotes CD8 Gene:925
3512 134079-134082 Gene denotes CD4 Gene:920
3513 134088-134091 Gene denotes CD8 Gene:925
3514 134399-134405 Gene denotes GM-CSF Gene:1437
3515 134410-134414 Gene denotes IL-6 Gene:3569
3516 134668-134672 Gene denotes IL-2 Gene:3558
3517 134674-134678 Gene denotes IL-6 Gene:3569
3518 134680-134684 Gene denotes IL-8 Gene:3576
3519 134686-134691 Gene denotes IL-10 Gene:3586
3520 134697-134702 Gene denotes TNF-α Gene:7124
3521 134807-134810 Gene denotes AST Gene:26503
3522 134872-134875 Gene denotes ALP Gene:10850
3523 134881-134884 Gene denotes GGT Gene:653590
3524 135457-135461 Gene denotes CCL5 Gene:6352
3525 135571-135576 Gene denotes IL-1β Gene:3552
3526 135578-135582 Gene denotes IL-6 Gene:3569
3527 135584-135588 Gene denotes IL-8 Gene:3576
3528 135611-135616 Gene denotes CXCL8 Gene:3576
3529 135618-135622 Gene denotes CCL4 Gene:6351
3530 135624-135628 Gene denotes CCL3 Gene:6348
3531 135860-135863 Gene denotes CD4 Gene:920
3532 135931-135935 Gene denotes IL-6 Gene:3569
3533 135940-135943 Gene denotes CRP Gene:1401
3534 136012-136022 Gene denotes fibrinogen Gene:2244
3535 136219-136222 Gene denotes IFN Gene:3439
3536 136380-136384 Gene denotes IL-6 Gene:3569
3537 136386-136391 Gene denotes IL1RA Gene:3557
3538 136393-136397 Gene denotes CCL2 Gene:6347
3539 136399-136403 Gene denotes CCL8 Gene:6355
3540 136404-136409 Gene denotes CXCL2 Gene:2920
3541 136411-136416 Gene denotes CXCL8 Gene:3576
3542 136418-136423 Gene denotes CXCL9 Gene:4283
3543 136429-136435 Gene denotes CXCL16 Gene:58191
3544 136565-136569 Gene denotes IL-6 Gene:3569
3545 136571-136575 Gene denotes IL-8 Gene:3576
3546 136581-136586 Gene denotes TNF-α Gene:7124
3547 136702-136706 Gene denotes IL-6 Gene:3569
3548 136708-136712 Gene denotes IL-8 Gene:3576
3549 136718-136723 Gene denotes TNF-α Gene:7124
3550 136950-136953 Gene denotes CRP Gene:1401
3551 137003-137006 Gene denotes CRP Gene:1401
3552 137285-137288 Gene denotes CRP Gene:1401
3553 137538-137541 Gene denotes CRP Gene:1401
3554 137616-137619 Gene denotes CRP Gene:1401
3555 137921-137924 Gene denotes CRP Gene:1401
3556 138130-138133 Gene denotes CD4 Gene:920
3557 138136-138139 Gene denotes CD8 Gene:925
3558 138259-138262 Gene denotes CD4 Gene:920
3559 138314-138317 Gene denotes CD8 Gene:925
3560 138355-138358 Gene denotes AST Gene:26503
3561 138360-138363 Gene denotes CRP Gene:1401
3562 138868-138874 Gene denotes CXCL10 Gene:3627
3563 138876-138881 Gene denotes CXCL9 Gene:4283
3564 138883-138887 Gene denotes CCL2 Gene:6347
3565 138893-138899 Gene denotes IL-1RA Gene:3557
3566 139281-139284 Gene denotes CD4 Gene:920
3567 139287-139290 Gene denotes CD8 Gene:925
3568 139368-139371 Gene denotes CD8 Gene:925
3569 139406-139409 Gene denotes CD8 Gene:925
3570 139441-139444 Gene denotes CD8 Gene:925
3571 139521-139524 Gene denotes CD4 Gene:404704
3572 139601-139604 Gene denotes CD8 Gene:925
3573 139688-139692 Gene denotes IL-6 Gene:3569
3574 139694-139699 Gene denotes TNF-α Gene:7124
3575 139701-139707 Gene denotes IL-17A Gene:3605
3576 139709-139714 Gene denotes IFN-γ Gene:3458
3577 139716-139721 Gene denotes MCP-1 Gene:6347
3578 139723-139728 Gene denotes IL-10 Gene:3586
3579 139730-139734 Gene denotes IL-4 Gene:3565
3580 139740-139744 Gene denotes IL-5 Gene:3567
3581 139932-139935 Gene denotes CRP Gene:1401
3582 140250-140253 Gene denotes CD8 Gene:925
3583 140321-140324 Gene denotes CD4 Gene:920
3584 140335-140338 Gene denotes CD4 Gene:920
3585 140347-140352 Gene denotes TGF-β Gene:7039
3586 140365-140368 Gene denotes CD4 Gene:920
3587 140417-140420 Gene denotes CD4 Gene:920
3588 140486-140491 Gene denotes CXCR3 Gene:2833
3589 140503-140508 Gene denotes TGF-β Gene:7039
3590 140653-140658 Gene denotes CD11a Gene:3683
3591 140683-140686 Gene denotes CD4 Gene:920
3592 140692-140695 Gene denotes CD8 Gene:925
3593 140964-140969 Gene denotes CD11a Gene:3683
3594 140985-140990 Gene denotes CD11a Gene:3683
3595 141307-141312 Gene denotes IL-10 Gene:3586
3596 141314-141318 Gene denotes CCL2 Gene:6347
3597 141319-141324 Gene denotes MCP-1 Gene:6347
3598 141326-141332 Gene denotes CXCL10 Gene:3627
3599 141333-141338 Gene denotes IP-10 Gene:3627
3600 141340-141344 Gene denotes CCL3 Gene:6348
3601 141345-141351 Gene denotes MIP-1A Gene:6348
3602 141357-141361 Gene denotes CCL4 Gene:6351
3603 141362-141367 Gene denotes MIP1B Gene:6351
3604 141409-141415 Gene denotes CXCL10 Gene:3627
3605 141417-141424 Gene denotes TNFSF10 Gene:8743
3606 141426-141431 Gene denotes TIMP1 Gene:7076
3607 141437-141441 Gene denotes IL18 Gene:3606
3608 141443-141447 Gene denotes AREG Gene:374
3609 141449-141453 Gene denotes NRG1 Gene:3084
3610 141455-141459 Gene denotes IL10 Gene:3586
3611 141710-141713 Gene denotes CD8 Gene:925
3612 142009-142014 Gene denotes IL-1β Gene:3552
3613 142016-142020 Gene denotes IL-6 Gene:3569
3614 142026-142030 Gene denotes IL-8 Gene:3576
3615 142087-142092 Gene denotes CXCL9 Gene:4283
3616 142094-142100 Gene denotes CXCL10 Gene:3627
3617 142105-142111 Gene denotes CXCL11 Gene:6373
3618 142206-142210 Gene denotes IL1B Gene:3553
3619 142212-142215 Gene denotes IL6 Gene:3569
3620 142217-142221 Gene denotes TNFA Gene:7124
3621 142245-142249 Gene denotes CCL2 Gene:6347
3622 142251-142255 Gene denotes CCL3 Gene:6348
3623 142257-142261 Gene denotes CCL4 Gene:6351
3624 142266-142270 Gene denotes CCL7 Gene:6354
3625 142391-142396 Gene denotes IL1RN Gene:3557
3626 142398-142402 Gene denotes IL1B Gene:3553
3627 142404-142410 Gene denotes CXCL17 Gene:284340
3628 142412-142417 Gene denotes CXCL8 Gene:3576
3629 142419-142424 Gene denotes CXCL1 Gene:2919
3630 142426-142431 Gene denotes CXCL2 Gene:2920
3631 142437-142441 Gene denotes CCL2 Gene:6347
3632 142443-142447 Gene denotes CCL7 Gene:6354
3633 142554-142560 Gene denotes S100A8 Gene:6279
3634 142562-142568 Gene denotes S100A9 Gene:6280
3635 142573-142580 Gene denotes S100A12 Gene:6283
3636 125061-125069 Species denotes patients Tax:9606
3637 125385-125393 Species denotes patients Tax:9606
3638 125732-125740 Species denotes patients Tax:9606
3639 125795-125803 Species denotes patients Tax:9606
3640 126008-126016 Species denotes patients Tax:9606
3641 126112-126120 Species denotes patients Tax:9606
3642 126127-126135 Species denotes patients Tax:9606
3643 126391-126399 Species denotes patients Tax:9606
3644 126582-126590 Species denotes patients Tax:9606
3645 126710-126718 Species denotes patients Tax:9606
3646 126893-126901 Species denotes patients Tax:9606
3647 127012-127020 Species denotes patients Tax:9606
3648 127148-127156 Species denotes patients Tax:9606
3649 127462-127470 Species denotes patients Tax:9606
3650 130070-130078 Species denotes patients Tax:9606
3651 130310-130318 Species denotes patients Tax:9606
3652 130676-130684 Species denotes patients Tax:9606
3653 130694-130702 Species denotes patients Tax:9606
3654 131720-131728 Species denotes patients Tax:9606
3655 131981-131989 Species denotes patients Tax:9606
3656 132549-132557 Species denotes patients Tax:9606
3657 132592-132600 Species denotes patients Tax:9606
3658 132778-132786 Species denotes patients Tax:9606
3659 133004-133012 Species denotes patients Tax:9606
3660 133371-133379 Species denotes patients Tax:9606
3661 134041-134049 Species denotes patients Tax:9606
3662 134214-134222 Species denotes patients Tax:9606
3663 134295-134303 Species denotes patients Tax:9606
3664 134334-134342 Species denotes patients Tax:9606
3665 134535-134543 Species denotes patients Tax:9606
3666 134582-134590 Species denotes patients Tax:9606
3667 134921-134929 Species denotes patients Tax:9606
3668 135096-135104 Species denotes patients Tax:9606
3669 135215-135223 Species denotes patients Tax:9606
3670 135501-135509 Species denotes patients Tax:9606
3671 136150-136160 Species denotes SARS-CoV-2 Tax:2697049
3672 136174-136184 Species denotes SARS-CoV-2 Tax:2697049
3673 136252-136259 Species denotes patient Tax:9606
3674 136622-136630 Species denotes patients Tax:9606
3675 136669-136677 Species denotes patients Tax:9606
3676 136908-136916 Species denotes patients Tax:9606
3677 137238-137246 Species denotes patients Tax:9606
3678 137571-137579 Species denotes patients Tax:9606
3679 138179-138187 Species denotes patients Tax:9606
3680 138938-138946 Species denotes patients Tax:9606
3681 139022-139030 Species denotes patients Tax:9606
3682 139076-139084 Species denotes patients Tax:9606
3683 139192-139200 Species denotes patients Tax:9606
3684 139245-139253 Species denotes patients Tax:9606
3685 139771-139779 Species denotes patients Tax:9606
3686 140239-140247 Species denotes patients Tax:9606
3687 140527-140535 Species denotes patients Tax:9606
3688 140743-140751 Species denotes patients Tax:9606
3689 140929-140937 Species denotes patients Tax:9606
3690 141116-141124 Species denotes patients Tax:9606
3691 141199-141207 Species denotes Patients Tax:9606
3692 141228-141236 Species denotes Patients Tax:9606
3693 141767-141774 Species denotes patient Tax:9606
3694 141937-141945 Species denotes patients Tax:9606
3695 142056-142064 Species denotes patients Tax:9606
3696 142146-142154 Species denotes patients Tax:9606
3697 142475-142483 Species denotes patients Tax:9606
3698 142693-142701 Species denotes patients Tax:9606
3699 136321-136332 Species denotes respiratory Tax:12814
3700 132298-132306 Species denotes patients Tax:9606
3701 132702-132710 Species denotes patients Tax:9606
3702 134756-134764 Species denotes patients Tax:9606
3703 127357-127366 Gene denotes myoglobin Gene:4151
3704 138992-138995 Gene denotes CRP Gene:1401
3705 138402-138405 Gene denotes CRP Gene:1401
3706 132262-132265 Gene denotes CRP Gene:1401
3707 139619-139622 Gene denotes CD4 Gene:920
3708 138560-138563 Gene denotes CD4 Gene:920
3709 128570-128573 Gene denotes CD4 Gene:920
3710 138569-138572 Gene denotes CD8 Gene:925
3711 128792-128795 Gene denotes CD8 Gene:925
3712 128313-128316 Gene denotes CD8 Gene:925
3713 126486-126496 Chemical denotes creatinine MESH:D003404
3714 126498-126508 Chemical denotes creatinine MESH:D003404
3715 127345-127355 Chemical denotes creatinine MESH:D003404
3716 127397-127406 Chemical denotes bilirubin MESH:D001663
3717 127418-127422 Chemical denotes urea MESH:D014508
3718 127423-127431 Chemical denotes nitrogen MESH:D009584
3719 127513-127523 Chemical denotes creatinine MESH:D003404
3720 127529-127539 Chemical denotes creatinine MESH:D003404
3721 132314-132324 Chemical denotes creatinine MESH:D003404
3722 132330-132340 Chemical denotes creatinine MESH:D003404
3723 133258-133267 Chemical denotes bilirubin MESH:D001663
3724 133269-133279 Chemical denotes creatinine MESH:D003404
3725 133285-133292 Chemical denotes lactate MESH:D019344
3726 134827-134837 Chemical denotes creatinine MESH:D003404
3727 134861-134870 Chemical denotes bilirubin MESH:D001663
3728 136034-136044 Chemical denotes creatinine MESH:D003404
3729 138369-138379 Chemical denotes creatinine MESH:D003404
3730 125205-125220 Disease denotes lymphocytopenia MESH:D008231
3731 125723-125731 Disease denotes COVID-19 MESH:C000657245
3732 125786-125794 Disease denotes COVID-19 MESH:C000657245
3733 126045-126060 Disease denotes lymphocytopenia MESH:D008231
3734 126649-126657 Disease denotes COVID-19 MESH:C000657245
3735 127644-127658 Disease denotes Critically ill MESH:D016638
3736 128049-128064 Disease denotes Lymphocytopenia MESH:D008231
3737 130061-130069 Disease denotes COVID-19 MESH:C000657245
3738 130667-130675 Disease denotes COVID-19 MESH:C000657245
3739 130851-130866 Disease denotes Lymphocytopenia MESH:D008231
3740 134286-134294 Disease denotes COVID-19 MESH:C000657245
3741 134503-134515 Disease denotes Leukocytosis MESH:D007964
3742 134640-134655 Disease denotes lymphocytopenia MESH:D008231
3743 135031-135036 Disease denotes Death MESH:D003643
3744 135276-135291 Disease denotes lymphocytopenia MESH:D008231
3745 135329-135337 Disease denotes COVID-19 MESH:C000657245
3746 135486-135500 Disease denotes critically ill MESH:D016638
3747 136493-136501 Disease denotes COVID-19 MESH:C000657245
3748 136613-136621 Disease denotes COVID-19 MESH:C000657245
3749 136692-136699 Disease denotes myeloma MESH:D009101
3750 136875-136883 Disease denotes COVID-19 MESH:C000657245
3751 136899-136907 Disease denotes COVID-19 MESH:C000657245
3752 137067-137075 Disease denotes COVID-19 MESH:C000657245
3753 137223-137237 Disease denotes critically ill MESH:D016638
3754 137327-137342 Disease denotes lymphocytopenia MESH:D008231
3755 138170-138178 Disease denotes COVID-19 MESH:C000657245
3756 138543-138551 Disease denotes COVID-19 MESH:C000657245
3757 138929-138937 Disease denotes COVID-19 MESH:C000657245
3758 139013-139021 Disease denotes COVID-19 MESH:C000657245
3759 139155-139170 Disease denotes lymphocytopenia MESH:D008231
3760 139236-139244 Disease denotes COVID-19 MESH:C000657245
3761 139762-139770 Disease denotes COVID-19 MESH:C000657245
3762 139849-139860 Disease denotes Lymphopenia MESH:D008231
3763 139862-139874 Disease denotes neutrophilia MESH:C563010
3764 139880-139896 Disease denotes thrombocytopenia MESH:D013921
3765 140224-140238 Disease denotes critically ill MESH:D016638
3766 140728-140742 Disease denotes critically ill MESH:D016638
3767 140900-140909 Disease denotes infection MESH:D007239
3768 141058-141066 Disease denotes COVID-19 MESH:C000657245
3769 141134-141148 Disease denotes critically ill MESH:D016638
3770 141752-141766 Disease denotes critically ill MESH:D016638
3771 142343-142351 Disease denotes COVID-19 MESH:C000657245
3772 142466-142474 Disease denotes COVID-19 MESH:C000657245
3773 142684-142692 Disease denotes COVID-19 MESH:C000657245
3775 142841-142876 Disease denotes Acute Respiratory Distress Syndrome MESH:D012128
3783 143069-143077 Species denotes patients Tax:9606
3784 143013-143028 Disease denotes lymphocytopenia MESH:D008231
3785 143060-143068 Disease denotes COVID-19 MESH:C000657245
3786 143151-143155 Disease denotes ARDS MESH:D012128
3787 143208-143214 Disease denotes deaths MESH:D003643
3788 143317-143321 Disease denotes ARDS MESH:D012128
3789 143355-143363 Disease denotes COVID-19 MESH:C000657245
3801 143845-143853 Species denotes patients Tax:9606
3802 143714-143725 Species denotes respiratory Tax:12814
3803 143739-143758 Disease denotes multi-organ failure MESH:D009102
3804 143827-143844 Disease denotes SARS-CoV infected MESH:C000657245
3805 143920-143931 Disease denotes lung damage MESH:D008171
3806 144290-144305 Disease denotes alveolar damage MESH:D055370
3807 144473-144488 Disease denotes pulmonary edema MESH:D011654
3808 144490-144500 Disease denotes thrombosis MESH:D013927
3809 144576-144592 Disease denotes SARS-CoV disease MESH:C000657245
3810 144695-144703 Disease denotes fibrosis MESH:D005355
3811 144877-144896 Disease denotes multi-organ failure MESH:D009102
3822 145175-145183 Species denotes patients Tax:9606
3823 145759-145767 Species denotes patients Tax:9606
3824 146347-146350 Chemical denotes ROS
3825 146405-146418 Chemical denotes peroxynitrite MESH:D030421
3826 145112-145120 Disease denotes COVID-19 MESH:C000657245
3827 145166-145174 Disease denotes COVID-19 MESH:C000657245
3828 145282-145290 Disease denotes Infected MESH:D007239
3829 145744-145758 Disease denotes critically ill MESH:D016638
3830 146541-146555 Disease denotes vascular edema MESH:D004487
3831 146602-146606 Disease denotes ARDS MESH:D012128
3847 146855-146860 Gene denotes TGF-β Gene:7039
3848 146978-146983 Gene denotes TGF-β Gene:7039
3849 147086-147097 Gene denotes fibronectin Gene:2335
3850 146752-146760 Species denotes patients Tax:9606
3852 147422-147429 Species denotes patient Tax:9606
3853 146622-146626 Disease denotes ARDS MESH:D012128
3854 146710-146719 Disease denotes mortality MESH:D003643
3855 146747-146751 Disease denotes ARDS MESH:D012128
3856 146822-146830 Disease denotes fibrosis MESH:D005355
3857 146927-146931 Disease denotes ARDS MESH:D012128
3858 147163-147171 Disease denotes fibrosis MESH:D005355
3860 147451-147459 Disease denotes COVID-19 MESH:C000657245
3861 147613-147617 Disease denotes ARDS MESH:D012128
3863 147649-147673 Disease denotes microvesicular steatosis MESH:D005234
3876 147821-147828 Species denotes patient Tax:9606
3877 148068-148076 Species denotes patients Tax:9606
3878 148189-148197 Species denotes patients Tax:9606
3879 148218-148226 Species denotes patients Tax:9606
3880 147845-147865 Disease denotes SARS-CoV-2 infection MESH:C000657245
3881 147904-147912 Disease denotes fibrosis MESH:D005355
3882 147981-147985 Disease denotes ARDS MESH:D012128
3883 148059-148067 Disease denotes COVID-19 MESH:C000657245
3884 148123-148131 Disease denotes Necrosis MESH:D009336
3885 148269-148274 Disease denotes edema MESH:D004487
3886 148281-148297 Disease denotes cell hyperplasia MESH:D006965
3887 148299-148309 Disease denotes thrombosis MESH:D013927
3909 148787-148811 Gene denotes alanine aminotransferase Gene:2875
3910 148884-148909 Gene denotes γ-glutamyl transpeptidase Gene:102724197
3911 148598-148606 Species denotes patients Tax:9606
3912 149169-149177 Species denotes patients Tax:9606
3913 149437-149445 Species denotes patients Tax:9606
3914 149883-149891 Species denotes patients Tax:9606
3915 148758-148768 Chemical denotes creatinine MESH:D003404
3916 148847-148856 Chemical denotes bilirubin MESH:D001663
3917 148616-148620 Disease denotes ARDS MESH:D012128
3918 148625-148648 Disease denotes multi-organ dysfunction MESH:D009102
3919 149012-149022 Disease denotes thrombosis MESH:D013927
3920 149141-149155 Disease denotes critically ill MESH:D016638
3921 149295-149318 Disease denotes multi-organ dysfunction MESH:D009102
3922 149326-149334 Disease denotes COVID-19 MESH:C000657245
3923 149420-149424 Disease denotes ARDS MESH:D012128
3924 149428-149436 Disease denotes COVID-19 MESH:C000657245
3925 149499-149509 Disease denotes thrombosis MESH:D013927
3926 149566-149570 Disease denotes ARDS MESH:D012128
3927 149775-149779 Disease denotes ARDS MESH:D012128
3928 149783-149791 Disease denotes COVID-19 MESH:C000657245
3929 149874-149882 Disease denotes COVID-19 MESH:C000657245
3941 150531-150535 Gene denotes ORF6 Gene:43740572
3942 150540-150544 Gene denotes ORF8 Gene:43740577
3943 150276-150284 Species denotes SARS-CoV Tax:694009
3944 150553-150561 Species denotes SARS-CoV Tax:694009
3945 150566-150576 Species denotes SARS-CoV-2 Tax:2697049
3946 150927-150935 Species denotes patients Tax:9606
3947 151016-151024 Species denotes patients Tax:9606
3948 150100-150108 Disease denotes COVID-19 MESH:C000657245
3949 150476-150496 Disease denotes SARS-CoV-2 infection MESH:C000657245
3950 150918-150926 Disease denotes COVID-19 MESH:C000657245
3951 150965-150980 Disease denotes lymphocytopenia MESH:D008231
3966 151713-151716 Gene denotes IL6 Gene:3569
3967 151726-151731 Gene denotes GMCSF Gene:1437
3968 151254-151262 Species denotes patients Tax:9606
3969 151901-151909 Species denotes patients Tax:9606
3970 152165-152173 Species denotes patients Tax:9606
3971 152577-152590 Species denotes coronaviruses Tax:11118
3972 152691-152701 Species denotes SARS-CoV-2 Tax:2697049
3973 153058-153066 Species denotes patients Tax:9606
3974 151864-151874 Chemical denotes remdesivir MESH:C000606551
3976 151245-151253 Disease denotes COVID-19 MESH:C000657245
3977 152071-152079 Disease denotes COVID-19 MESH:C000657245
3978 152636-152645 Disease denotes infection MESH:D007239
3979 153049-153057 Disease denotes COVID-19 MESH:C000657245
3983 153523-153533 Species denotes SARS-CoV-2 Tax:2697049
3984 153376-153380 Disease denotes ARDS MESH:D012128
3985 153390-153392 Disease denotes MJ MESH:D009207
5161 53065-53067 Chemical denotes CD MESH:D002104
5163 154270-154308 Gene denotes cutaneous T-cell -attracting chemokine Gene:10850
5166 154326-154327 Chemical denotes C MESH:D002244
5167 154330-154331 Chemical denotes C MESH:D002244
5169 154592-154595 Chemical denotes LMR
5171 154871-154873 Chemical denotes SP MESH:C000604007
5173 154913-154916 Gene denotes TIM Gene:26762
5175 155019-155033 Disease denotes Tumor necrosis MESH:D009336
5177 155050-155103 Gene denotes tumor necrosis factor (ligand) superfamily, member 10 Gene:7124

LitCovid-sentences

Id Subject Object Predicate Lexical cue
T1 0-9 Sentence denotes COVID-19:
T2 10-76 Sentence denotes The Emerging Immunopathological Determinants for Recovery or Death
T3 78-86 Sentence denotes Abstract
T4 87-211 Sentence denotes Hyperactivation of the host immune system during infection by SARS-CoV-2 is the leading cause of death in COVID-19 patients.
T5 212-359 Sentence denotes It is also evident that patients who develop mild/moderate symptoms and successfully recover display functional and well-regulated immune response.
T6 360-562 Sentence denotes Whereas a delayed initial interferon response is associated with severe disease outcome and can be the tipping point towards immunopathological deterioration, often preceding death in COVID-19 patients.
T7 563-652 Sentence denotes Further, adaptive immune response during COVID-19 is heterogeneous and poorly understood.
T8 653-812 Sentence denotes At the same time, some studies suggest activated T and B cell response in severe and critically ill patients and the presence of SARS-CoV2-specific antibodies.
T9 813-991 Sentence denotes Thus, understanding this problem and the underlying molecular pathways implicated in host immune function/dysfunction is imperative to devise effective therapeutic interventions.
T10 992-1144 Sentence denotes In this comprehensive review, we discuss the emerging immunopathological determinants and the mechanism of virus evasion by the host cell immune system.
T11 1145-1403 Sentence denotes Using the knowledge gained from previous respiratory viruses and the emerging clinical and molecular findings on SARS-CoV-2, we have tried to provide a holistic understanding of the host innate and adaptive immune response that may determine disease outcome.
T12 1404-1644 Sentence denotes Considering the critical role of the adaptive immune system during the viral clearance, we have presented the molecular insights of the plausible mechanisms involved in impaired T cell function/dysfunction during various stages of COVID-19.
T13 1646-1658 Sentence denotes Introduction
T14 1659-1921 Sentence denotes Following reports of severe pneumonia cases of unknown etiology from Wuhan, China, multiple groups identified the pathogenic agent responsible for the current COVID-19 pandemic as the SARS-CoV-2 virus (Chan et al., 2020; Huang C. et al., 2020; Zhu et al., 2020).
T15 1922-2122 Sentence denotes The last several months have seen an unprecedented surge in research efforts to understand the underlying molecular mechanisms associated with SARS-CoV-2 infectivity, immunogenicity, and pathogenesis.
T16 2123-2396 Sentence denotes Since it is now evident that SARS-CoV-2 employs the same set of receptors and host cells, previously utilized by SARS-CoV, various disease models were developed to understand the molecular networks implicated in viral evasion, host immune response, and immuno-pathogenesis.
T17 2397-2578 Sentence denotes Multiple factors and pathways are already known based on previous knowledge from other coronaviruses, which have shown promising potential as therapeutic targets (Tay et al., 2020).
T18 2579-2798 Sentence denotes But a more comprehensive understanding to develop highly effective therapies is yet to emerge, which demands better molecular details at various stages of the virus propagation and disease progression in the host cells.
T19 2799-3025 Sentence denotes In the initial early mild phase of infection (Stage I), the virus remains confined to the upper respiratory tract (nasal cells, some areas of pharynx and larynx) which elicits low levels of the innate immune response (if any).
T20 3026-3183 Sentence denotes This asymptomatic state lasts for a couple of days (generally one or two days) before the virus propagates to the conducting and terminal airways (Stage II).
T21 3184-3314 Sentence denotes During this stage of the disease, an optimal but controlled adaptive and innate immune response will help to combat the infection.
T22 3315-3519 Sentence denotes Successful viral clearance from recovered patients, show the presence of adequate adaptive immune cells along with the immunomodulatory molecules and neutralizing antibodies (Cao, 2020; Tay et al., 2020).
T23 3520-3773 Sentence denotes However, an impaired adaptive immune response at this stage, with concomitant overactivation of the innate immune system (inflammatory macrophages and neutrophils) can lead to severe disease symptoms in ∼20% of COVID-19 patients (Wu and McGoogan, 2020).
T24 3774-3979 Sentence denotes Recent clinical and histopathological data from deceased patients suggest adaptive immune dysfunction and heightened proinflammatory response with inflammatory cell infiltration into the lungs (Stage III).
T25 3980-4195 Sentence denotes Further, the disease severity positively correlated with increased levels of proinflammatory IL-6 and an increase in the neutrophil/lymphocyte ratio (Liu T. et al., 2020; Tan L. et al., 2020b; Tan M. et al., 2020c).
T26 4196-4497 Sentence denotes Between 3 and 17% of COVID-19 patients developed acute respiratory distress syndrome (ARDS), as a result of hyper inflammation (excessive infiltration of activated innate immune cells and cytokine release syndrome) and lymphocytopenia (reduced levels of CD4+, CD8+, and B cells) (Gibson et al., 2020).
T27 4498-4768 Sentence denotes These changes are followed by cell death and tissue destruction, which ultimately leads to airway collapse, multiple organ failure and death in 67–85% of ICU patients, based on the available data so far (Wu and McGoogan, 2020; Xu Z. et al., 2020; Zhang H. et al., 2020).
T28 4769-4932 Sentence denotes Here, we discuss the molecular determinants implicated in the success or failure of recovery through various phases of immune response generated by the host cells.
T29 4933-5210 Sentence denotes We have built an immunological trajectory of COVID-19 patients who have successfully cleared the virus against those who have developed severe symptoms, with emphasis on virus sensing and evasion mechanisms, and the spatiotemporal role of the innate and adaptive immune system.
T30 5211-5311 Sentence denotes Further, we provided cellular and molecular details of cytokine storm and ARDS in COVID-19 patients.
T31 5313-5369 Sentence denotes Innate Nucleic Acid Sensing and Viral Evasion Mechanisms
T32 5371-5414 Sentence denotes Nucleic Acid Sensors in Antiviral Signaling
T33 5415-5570 Sentence denotes SARS-CoV-2, like its predecessor SARS-CoV, employs spike (S) protein to enter into the eukaryotic cells by binding to the surface-expressed ACE2 receptors.
T34 5571-5898 Sentence denotes Upon binding, S protein priming takes place by the membrane expressed protease TMPRSS2 or endosomal proteases such as cathepsin, elastase, and furin (which is specific to SARS-CoV-2) to induce fusion between the viral and host cell membrane (Hoffmann et al., 2020; Shang et al., 2020; Walls et al., 2020; Wang Q. et al., 2020).
T35 5899-6176 Sentence denotes Following these well-coordinated events, viral genetic material will release in a biphasic manner, i.e. either by direct fusion with the plasma membrane or by following the endocytic route as shown previously for SARS-CoV (Belouzard et al., 2012; Shang et al., 2020; Figure 1).
T36 6177-6595 Sentence denotes An increasing list of cell types appear directly infected by the SARS-CoV-2, which include the alveolar epithelial type II cell (ATII) as the principal targets, and other cell types lining various tissues such as bronchial epithelial cells in lungs, goblet cells in the nasal cavity, macrophages, esophageal cells, pancreatic β-cells, and gastrointestinal epithelial cells (Li M.Y. et al., 2020; Sungnak et al., 2020).
T37 6596-6690 Sentence denotes All these cell types express the S protein target receptor ACE2, albeit with lower expression.
T38 6691-6838 Sentence denotes However, ATII cells remain the predominant targets for SARS-CoV-2 as for SARS-CoV, which are involved in the sensing of the various viral proteins.
T39 6839-6904 Sentence denotes FIGURE 1 Proposed model of SARS-CoV-2 entry into the host cells.
T40 6905-7158 Sentence denotes Based on available literature on SARS-CoV and recent findings on SARS-CoV-2, we suggest two different mechanisms that can be employed by SARS-CoV-2 to enter into the ACE2 expressing cells. (1) Initially the virus may use the cell membrane mode of entry.
T41 7159-7402 Sentence denotes The first step is the binding of the spike protein of the virus with ACE2 receptors expressed on the plasma membrane of host cells. (2) The attachment with ACE2 is followed by the cleavage of S protein by membrane bound proteases like TMPRSS2.
T42 7403-7985 Sentence denotes TMPRSS2 cleaves the membrane bound virus at both S1/S2 boundary as well as at S2’ site. (3) This activates the fusion machinery, and subsequently, the viral membrane fuses with the host cell plasma membrane. (4) This leads to release of the viral nucleocapsid into the cytoplasm. (5) The replication, assembly, and maturation of virus takes places in the cytoplasm. (6) Before dissemination, SARS-CoV-2 may also undergo pre-activation in the golgi apparatus by furin proteases. (7) The fully mature and pre-activated SARS-CoV-2 eventually disseminates from host cells by exocytosis.
T43 7986-8115 Sentence denotes During subsequent infection cycles, the virus may utilize either cell membrane or (8–11) the more probable endocytic entry route.
T44 8116-8478 Sentence denotes In the endocytic mode of entry, (8) after attachment with ACE2, (9) the virus gets endocytosed and (10) then processed at the S2’ region by endosomal proteases like cathepsins, to activate membrane fusion. (11) Finally, the viral components are released into the cytoplasm by fusion of the viral membranes with endosomal membrane, leading to repeat of the cycle.
T45 8479-8701 Sentence denotes Preceding studies on human infecting coronaviruses (CoVs) have demonstrated a critical role of nucleic acid-sensing (NAS) pathways in recognizing various components of these viruses to initiate an early antiviral response.
T46 8702-8850 Sentence denotes Whereas, potent inhibitory mechanisms are developed by CoVs to prevent or delay early antiviral responses (Rose et al., 2010; Adedeji et al., 2013).
T47 8851-8949 Sentence denotes These inhibitory signals affect a range of host defense pathways to allow the propagation of CoVs.
T48 8950-9052 Sentence denotes Some inhibitory signals may even activate cell death pathway to induce a robust proinflammatory state.
T49 9053-9380 Sentence denotes Studies from in vitro cell culture, animal models, and patients who have successfully recovered from SARS-CoV infection have provided detailed molecular insights about signaling molecules implicated in virus-host interaction that may also serve as a model to understand a similar process in SARS-CoV-2 (Totura and Baric, 2012).
T50 9381-9588 Sentence denotes After release into the cytoplasm, the ssRNA viral genomes of SARS-CoV and SARS-CoV-2 proceed to replication via a double-stranded RNA (dsRNA) intermediate state (Adedeji et al., 2012; Cascella et al., 2020).
T51 9589-9753 Sentence denotes Both ssRNA and dsRNA act as pathogen-associated molecular patterns (PAMPs) which are recognized by pathogen recognition receptors (PRRs; Leiva-Juárez et al., 2018).
T52 9754-9936 Sentence denotes ATII cells are known to express key endogenous PRRs like Toll-like receptors (TLRs), cyclic GMP–AMP synthase (cGAS); and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs).
T53 9937-10141 Sentence denotes Among these, cytosolic RLRs and endosomal TLRs (TLR3, TLR7, TLR8, TLR9) have a prominent role in initiating the antiviral response by sensing RNA from SARS-CoVs (Lester and Li, 2014; Chan and Gack, 2016).
T54 10142-10395 Sentence denotes RLRs are a complex of sensor proteins that include RIG-I, melanoma differentiation-associated gene 5 (MDA5), and the more recently discovered probable ATP-dependent RNA helicase DHX58 (also known as LGP2) (Jiang et al., 2011; Leiva-Juárez et al., 2018).
T55 10396-10501 Sentence denotes RIG-I binds to 5’-PPP RNA and short dsRNA, while MDA5 binds to longer RNA fragments (Huang et al., 2014).
T56 10502-10651 Sentence denotes Binding of pathogenic RNAs induces conformational changes in RIG-I and MDA5, and after that post-translational modifications activate these proteins.
T57 10652-11010 Sentence denotes Importantly, RIG-I is activated by E3 ligase tripartite motif protein 25 (TRIM25) via polyubiquitination at K172 residue (Sanchez et al., 2016); MDA5 is proteolytically inactivated by the polyubiquitination mediated by poly (rC) binding protein 2 (PCBP2) with assistance from AIP4/ITCH (Atrophin 1 Interacting Protein 4; also called ITCH) (You et al., 2009).
T58 11011-11102 Sentence denotes LGP2 acts as a facilitator to enhance viral sensing by RIG-1 and MDA5 (Satoh et al., 2010).
T59 11103-11338 Sentence denotes Activated RIG-I and MDA5 then mount the downstream signaling cascade via centrally placed mitochondrial antiviral signaling protein (MAVS) and eventually lead to the coordinated activation of IRF3/IRF7 transcription factors (Figure 2).
T60 11339-11519 Sentence denotes Activated IRF3/7 translocates to the nucleus and induces expression of IFNs via IFN-stimulated response element (ISRE) reviewed by West et al. (2011) and Rehwinkel and Gack (2020).
T61 11520-11741 Sentence denotes Thus, centrally placed MAVS activation induces expression of IFN genes via IRF3 and IRF7 pathways and recruitment of other innate immune cells, majorly by proinflammatory molecules secreted via NF κB signaling (Figure 2).
T62 11742-11925 Sentence denotes Similarly, activation of endogenous TLR pathway induces expression of IFN type I, type III, and more specifically, proinflammatory molecules via the NF κB pathway (Gong et al., 2020).
T63 11926-12143 Sentence denotes Blocking of either IRF3/7 or NF κB pathway has a detrimental effect on host cells that invariably allows propagation of the virus (Lazear et al., 2013; Schmitz et al., 2014; Totura et al., 2015; Chiang and Liu, 2019).
T64 12144-12289 Sentence denotes In animal studies, mice that are deficient in TLR signaling exhibit robust infection and severe pathological condition during SARS-CoV infection.
T65 12290-12429 Sentence denotes TLR3 and TLR4 knockout mice exhibited increased viral titers associated with lung damage and a higher mortality rate (Totura et al., 2015).
T66 12430-12639 Sentence denotes Mice with a knockout of myeloid differentiation primary response 88 (MYD88), which acts downstream of TLR signaling had increased damage to the lung parenchyma with a 90% mortality rate (Sheahan et al., 2008).
T67 12640-12926 Sentence denotes Conversely, activation of endogenous TLR signaling by TLR7, TLR8, and TLR9 or cell surface-expressed TLR4 signaling was associated with a significant decrease in viral propagation, attenuated lung damage, and increased the survival rate in SARS-CoV infected animals (Zhao et al., 2012).
T68 12927-13075 Sentence denotes These findings thus point to an integral role of these molecular sensors in mounting early protective antiviral response and aiding viral clearance.
T69 13076-13290 Sentence denotes FIGURE 2 Molecular and signaling pathway implicated in host cell antiviral response. (A) After the viral contents are released into the cytoplasm, the viral RNA is recognized by host cell NASs like RIG-I and MDA5.
T70 13291-13411 Sentence denotes Counter-defense may be provided by the viral proteins, NSP14 and NSP16 to shield the viral RNA from sensing by the NASs.
T71 13412-13554 Sentence denotes However, if successfully recognized, RIG-I and MDA5 get activated and subsequently activate the centrally placed MAVS located on mitochondria.
T72 13555-13622 Sentence denotes MAVS acts as a molecular adaptor that further recruits TRAF2/3/5/6.
T73 13623-13751 Sentence denotes Association of the type of TRAF with MAVS is suggested to determine the type of downstream signaling, i.e., IRF3/7 and/or NF-κB.
T74 13752-13845 Sentence denotes At the MAVS junction, the association of TRAF5/6 with TRADD, FADD, and RIPK1 activates NF-κB.
T75 13846-14015 Sentence denotes Whereas, binding of MAVS with STING activates TBK1 and IKKε by interacting with TRAF2/3, which eventually results in the activation of IRF3 and IRF7 (Chen et al., 2014).
T76 14016-14307 Sentence denotes Activated IRF3, IRF7, and NF-κB translocate to the nucleus and induce the expression of IFN genes. (B) The transcribed IFNs act on the respective IFN receptors (IFNRs) present on the host cells as well as on other innate immune cells, thus signaling in a both autocrine and paracrine manner.
T77 14308-14417 Sentence denotes Signaling via IFNRs activates the JAK/STAT signaling pathway and subsequently induces the expression of ISGs.
T78 14418-14491 Sentence denotes These molecular events were recently reviewed (Rehwinkel and Gack, 2020).
T79 14492-14551 Sentence denotes ISGs transcribed will eventually inhibit viral propagation.
T80 14552-14693 Sentence denotes However, SARS-CoV and likely SARS-CoV-2 have developed counter-defense mechanisms to interfere at various steps in the NAS signaling pathway.
T81 14694-14756 Sentence denotes NSP4a inhibits TRIM25, which is required for RIG-I activation.
T82 14757-14983 Sentence denotes N protein inhibits MDA5, NSP14 inhibits MAVS, ORF9b inhibits RIG-I/MDA5 activation complex, M protein interferes with TANK, IKKε, and TBK1 signaling, and PLpro inhibits various RIG-I, MDA5, and MAVs downstream signaling steps.
T83 14984-15087 Sentence denotes SARS-CoV-2 proteins acting at various steps in blocking NAS and IFN signaling are shown in the red box.
T84 15088-15658 Sentence denotes NAS, Nucleic acid sensors; RIG-I, Retinoic acid-inducible gene I; MDA5, melanoma differentiation-associated protein 5; TRAF, TNF receptor-associated factor; STING, ER-associated stimulator of interferon genes; FADD, FAS-associated death domain protein; IRF, Interferon regulatory factor (IRF3/7); TRADD, TNFR1-associated death domain protein; IKKε, IκB kinase-ε; RIPK1, Receptor-interacting protein 1; TANK, TRAF family member-associated NF-kappa-B activator; TBK1, TANK-binding kinase 1; ISG, Interferon stimulatory gene; TRIM25, Tripartite motif-containing protein 25.
T85 15659-15869 Sentence denotes The role of these molecular sensors is not yet comprehensively studied in SARS-CoV-2, but a few recent reports suggest that these sensors are similarly involved in the early antiviral response during infection.
T86 15870-16075 Sentence denotes The immunoinformatic approach revealed the presence of a wide range of ssRNA SARS-CoV-2 genome fragments as potential molecular PAMPs which were presumed to mediate signaling via endogenous TLR7/8 pathway.
T87 16076-16313 Sentence denotes Further, it is appearing that the number of PAMPs (genomic fragments) was higher in the SARS-CoV-2 genome as compared to SARS-CoV, suggesting that SARS-CoV-2 may drive relatively more robust immune response (Moreno-Eutimio et al., 2020).
T88 16314-16551 Sentence denotes Single-cell RNA-sequencing (scRNA-seq) study in PBMCs derived from ICU patients revealed extensive upregulation of NAS pathway genes including RIG-I, MDA5, and LGP2, suggesting an invasion of SARS-CoV-2 in these cells (Wei et al., 2020).
T89 16552-16653 Sentence denotes However, no direct assays were performed in these cells to find the presence or absence of viral RNA.
T90 16654-16902 Sentence denotes These findings may imply that that the SARS-CoV-2, does not directly infect PBMCs and thus this upregulation of NAS genes may be through passive uptake of the virus, most probably by antibody-dependent enhancement (ADE), as will be discussed later.
T91 16903-17011 Sentence denotes Similarly, endogenous TLR7 and TLR8 upregulate along with an increase in expression of MAVS, IRF3, and IRF7.
T92 17012-17251 Sentence denotes The functional importance of this upregulated expression of NAS pathway genes remains unclear and hence more research in this direction will clarify the specific role of these molecular sensors in the antiviral response against SARS-CoV-2.
T93 17253-17293 Sentence denotes Evasions Mechanism Employed by SARS-CoVs
T94 17294-17405 Sentence denotes All human infecting SARS-CoVs are known to have evolved multiple mechanisms to evade recognition by host cells.
T95 17406-17534 Sentence denotes Emerging evidence suggests that similar mechanisms are employed by SARS-CoV-2 to inhibit or delay the host cell immune response.
T96 17535-17584 Sentence denotes Some of these mechanisms will be discussed below.
T97 17586-17653 Sentence denotes Interference With the Nucleic Acid Sensing and Downstream Signaling
T98 17654-17842 Sentence denotes Previous studies on SARS-CoV revealed smart strategies to inhibit multiple steps in the NAS pathway and downstream signaling (Rose et al., 2010; Adedeji et al., 2013; Chan and Gack, 2016).
T99 17843-17912 Sentence denotes As mentioned earlier, TRIM25 mediated ubiquitination activates RIG-I.
T100 17913-18040 Sentence denotes Whereas, the N protein of SARS-CoV, which binds to TRIM25 and thereby prevents its association with RIG-I and hence activation.
T101 18041-18165 Sentence denotes The ubiquitin usurped RIG-I is unable to mount the antiviral response, thereby disabling IFN-β production (Hu et al., 2017).
T102 18166-18381 Sentence denotes N protein also antagonizes IFN signaling by directly interacting with IRF3, thereby inhibiting its phosphorylation and subsequent nuclear translocation (Kopecky-Bromberg et al., 2006; Kopecky-Bromberg et al., 2007).
T103 18382-18529 Sentence denotes Similarly, M protein inhibits IRF3/IRF7 signaling by interfering with RIG-I, TBK1, IKKε, and TRAF3 activation complex formation (Siu et al., 2009).
T104 18530-18758 Sentence denotes Acting at multiple pathways on host cells, Nsp1 inhibits IFN-β promoter activity and STAT1 phosphorylation which led to a decrease in the expression of various antiviral interferon-stimulated genes (ISGs; Wathelet et al., 2007).
T105 18759-18929 Sentence denotes Chen et al. (2014) showed that papain-like protease (PLpro) directly associates with TRAF3, TBK1, IKKε, STING, and IRF3 and hence inhibits downstream IRF3/IRF7 signaling.
T106 18930-19059 Sentence denotes In another study, Devaraj et al. (2007) showed that PLpro inhibits IRF3 phosphorylation and its subsequent nuclear translocation.
T107 19060-19265 Sentence denotes ORF3b, ORF6, ORF8a, and ORF8b also play prominent roles in inhibiting IRF3 phosphorylation and its subsequent nuclear translocation (Kopecky-Bromberg et al., 2006; Freundt et al., 2010; Wong et al., 2018).
T108 19266-19455 Sentence denotes ORF9b was shown to be associated with mitochondria and induced degradation of dynamin-related protein 1 (Drp1), thus altering mitochondrial function and sequestering MAVS into small puncta.
T109 19456-19669 Sentence denotes Further, ORF9b was associated with recruitment of ubiquitin ligases PCBP2 and AIP4 E3 which led to ubiquitination of MAVS and eventually its degradation, as a result inhibiting IFN-β production (Shi et al., 2014).
T110 19670-19824 Sentence denotes Thus, by associating with multiple proteins involved in NAS signaling, SARS-CoV antagonizes IFN signaling and synthesis of protective molecules like ISGs.
T111 19825-19979 Sentence denotes Recent studies have also demonstrated the interaction of SARS-CoV-2 proteins with multiple host cell NAS signaling molecules and downstream IFN signaling.
T112 19980-20104 Sentence denotes An extensive proteomic study by Gordon et al. (2020), showed multiple SARS-CoV-2 protein and host cell protein interactions.
T113 20105-20203 Sentence denotes A proteome map of 26 SARS-CoV-2 proteins predicted 332 viral proteins interacting with host cells.
T114 20204-20347 Sentence denotes Among these, Nsp9, Nsp13, Nsp15, ORF3a, ORF9b, and ORF9c interacted with proteins in downstream NAS signaling, IFN response, and NF-κB pathway.
T115 20348-20563 Sentence denotes Similarly, Nsp5 interacted with HDAC2, which may be thus involved in limiting the IFN signaling and inflammatory response, but the specific functional role of these proteins was not determined (Gordon et al., 2020).
T116 20564-20658 Sentence denotes In two recent studies, the functional relevance of some of these proteins was tested in vitro.
T117 20659-20849 Sentence denotes In the first study, Li J.Y. et al. (2020) tested the effects of ORF6, ORF8 and N protein on the antiviral response in HEK293 cells and found these proteins inhibit IFN-β and NF-κB signaling.
T118 20850-21017 Sentence denotes Similarly, Yuen et al. (2020) showed that IFN antagonizing effect of ORF6 was due to its association with the interferon-inducible nuclear export complex (NUP98–RAE1).
T119 21018-21163 Sentence denotes The study further showed that Nsp13, Nsp14, and Nsp15 could also antagonize IFN response, but the mechanism was not explored (Yuen et al., 2020).
T120 21164-21296 Sentence denotes In addition to interfering with IFN production pathway, SARS-CoV has evolved multiple other mechanisms to modify host cell response.
T121 21297-21446 Sentence denotes Viral RNA is unprotected and open to cellular degradation; however, some RNA viruses have evolved a capping process to evade recognition by the host.
T122 21447-21599 Sentence denotes In SARS-CoV, Nsp16 provides ribose 2′-O-methylation at the 5′ end of the RNA to protect its degradation and prevent sensing by MDA5 (Züst et al., 2011).
T123 21600-21708 Sentence denotes Similarly, Nsp14 had N7 methyltransferase activity and methylated the 5′ end of the RNA (Chen et al., 2009).
T124 21709-21868 Sentence denotes Other SARS-CoV proteins involved include – Nsp4a, which prevents stress granule formation by inhibiting PKR mediated antiviral signaling (Rabouw et al., 2016).
T125 21869-21999 Sentence denotes N protein of SARS-CoV-2 is also known to interact with the proteins implicated in stress granule regulation (Gordon et al., 2020).
T126 22000-22233 Sentence denotes Electron tomography studies in SARS-CoV infected cells revealed a unique replication network derived from ER to organize viral replication while simultaneously hiding the viral RNA from recognition by host NASs (Knoops et al., 2008).
T127 22234-22440 Sentence denotes Other RNA viruses have also developed similar strategies to evade sensing by forming double-membrane vesicles (DMVs) and replication organelles to prevent access to the NASs (Blanchard and Roingeard, 2015).
T128 22442-22516 Sentence denotes Inhibition of Host Cell Biosynthetic Pathways and Modulation of Cell Death
T129 22517-22621 Sentence denotes Both SARS-CoV and SARS-CoV-2 have evolved multiple inhibitory mechanisms to evade host cell recognition.
T130 22622-22781 Sentence denotes Inhibition of host transcriptional and translational machinery prevents the biosynthesis of protective IFNs and delays early activation of host cell apoptosis.
T131 22782-22886 Sentence denotes Nsp1 of SARS-CoV inhibit the loading of ribosomal 40s subunit and prevent host cell protein translation.
T132 22887-23031 Sentence denotes Further, Nsp1 specifically degrade host cell RNA while sparing the viral RNA (Huang et al., 2011; Tanaka et al., 2012; Lokugamage et al., 2015).
T133 23032-23135 Sentence denotes N protein of SARS-CoV-2 also interacts with the host biosynthetic protein La-related protein 1 (LARP1).
T134 23136-23288 Sentence denotes This interaction may serve as the necessary signal to shut down the host cell protein synthesis for the propagation of SARS-CoV-2 (Gordon et al., 2020).
T135 23289-23511 Sentence denotes Papain-like protease of SARS-CoV directly interacts with p53 and induce its degradation, which may thus interfere with translation and delay early apoptosis of the infected cells (Yuan et al., 2015; Ma-Lauer et al., 2016).
T136 23512-23678 Sentence denotes SARS-CoV S protein also interacts with the translation initiation factor eIF3f and inhibit host cell translation by preventing its nuclear import (Xiao et al., 2008).
T137 23679-23918 Sentence denotes Studies from other respiratory viruses have shown that cells which activate early apoptosis prevent further spread of the viruses, whereas viruses that successfully inhibit this pathway exhibit strong infectivity (Orzalli and Kagan, 2017).
T138 23919-24110 Sentence denotes Cytomegaloviruses (CMVs) distinctly rely on this mechanism to successfully replicate within the host cell by inhibiting apoptosis-modulatory proteins such as Bax and Bcl-2 (Çam et al., 2010).
T139 24111-24337 Sentence denotes However, whether SARS-CoV or SARS-CoV-2 are also directly involved in inhibiting early apoptosis remains to be tested, but it is evident that these viruses induce host cell death after successful propagation and dissemination.
T140 24338-24464 Sentence denotes SARS-CoV Nsp7a was shown to interact with prosurvival protein Bcl-X and induce apoptosis in cells in vitro (Tan et al., 2007).
T141 24465-24598 Sentence denotes Similarly, ORF3a leads to fragmentation of the Golgi apparatus, and induction of apoptosis (Waye et al., 2005; Freundt et al., 2010).
T142 24599-24747 Sentence denotes Besides this, ORF3a also implicates necroptotic cell death by interacting with and activating the main necroptosis protein RIPK3 (Yue et al., 2018).
T143 24748-24848 Sentence denotes Owing to its role in cell death pathways, the ORF3a of SARS-CoV-2 was also explored in this context.
T144 24849-24971 Sentence denotes This protein similarly induced apoptosis in HEK293 cells by activating the caspase 8-dependent pathway (Ren et al., 2020).
T145 24972-25205 Sentence denotes Interestingly, the results, that ORF3a of SARS-CoV-2 induces relatively lower apoptosis in several cell lines as compared to SARS-CoV, suggesting that this mechanism could provide an early advantage for the propagation of SARS-CoV-2.
T146 25206-25426 Sentence denotes Further, the proteome map of SARS-CoV-2 predicted interaction of Nsp12 with RIPK1, suggesting that this viral protein may also implicate in regulating host cell apoptotic and necroptotic cell death (Gordon et al., 2020).
T147 25427-25696 Sentence denotes However, a study on 25 cell lines in culture showed SARS-CoV-2 exhibiting cytopathic effect on only two cells, indicating that the differences could exist between these two related viruses in their property to interfere with host cell death pathways (Chu et al., 2020).
T148 25697-25886 Sentence denotes Thus, more comprehensive studies are needed to provide better molecular insights by which SARS-CoV-2 modulates host cell death pathways, which may also open new opportunities for treatment.
T149 25887-26155 Sentence denotes Based on these early observations, it is becoming evident that SARS-CoV-2 interferes with host NAS, IFN, biosynthetic, and cell death pathways to prevent early immune response and thus contribute to the underlying immunopathogenesis, as will be discussed subsequently.
T150 26156-26353 Sentence denotes To make these details simple, here we compiled the role of various SARS-CoV and SARS-CoV-2 proteins and their host cell interacting proteins and presented in the Table form (Supplementary Table 1).
T151 26355-26389 Sentence denotes Innate Immune Response in COVID-19
T152 26391-26424 Sentence denotes Functional Innate Immune Response
T153 26425-26690 Sentence denotes A balance between successful evasion of the virus from host cell sensing pathways and the counter mechanisms developed by the host cells to overcome these inhibitory effects determines whether an early immune response could be generated or not (Liang et al., 2020).
T154 26691-26895 Sentence denotes Though most of the studies point towards the successful evasion mechanisms employed by CoVs, emerging evidence suggests that an adequate early antiviral response could be mounted (Park and Iwasaki, 2020).
T155 26896-27101 Sentence denotes That early response may hold the key for limiting the viral propagation in the majority of the COVID-19 patients (approx 80%) who are asymptomatic or develop mild symptoms and successfully clear the virus.
T156 27102-27236 Sentence denotes Considered the recent work on COVID-19, here we provide a detailed molecular and clinical understanding of the innate immune response.
T157 27237-27369 Sentence denotes We specifically discuss how these immune responses dictate the recovery from disease or development of the immunopathological state.
T158 27371-27390 Sentence denotes Interferon Response
T159 27391-27562 Sentence denotes By initiating an early antiviral response, signaling via IFNs and ISGs is critical for the viral clearance and an impediment for the development of the pathological state.
T160 27563-27683 Sentence denotes Several in vitro and animal studies have established the central role of these signaling pathways in SARS-CoV infection.
T161 27684-27916 Sentence denotes STAT1 knockout mice infected with SARS-CoV exhibited severe disease symptoms, conferred by increased viral replication and propagation and was further associated with reduced survival rate (Hogan et al., 2004; Frieman et al., 2010).
T162 27917-28122 Sentence denotes Similarly, SARS-CoV propagation increases in IFNR1-/- and ILFNLR1/- double knockout mice, suggesting an essential role of these signaling pathways in mitigating antiviral response (Mahlakõiv et al., 2012).
T163 28123-28235 Sentence denotes Recent in vitro studies point to a more robust IFN response generated by SARS-CoV-2 compared to its predecessor.
T164 28236-28342 Sentence denotes Epithelial cells infected with SARS-CoV-2 displayed better IFN response than cells infected with SARS-CoV.
T165 28343-28468 Sentence denotes This IFN response was STAT1 phosphorylation-dependent with subsequent expression of antiviral ISGs (Lokugamage et al., 2020).
T166 28469-28734 Sentence denotes In line with these in vitro findings, transcriptome data from bronchial alveolar lavage fluid (BALF) taken from 8 COVID-19 patients revealed extensive upregulation of about 83 ISGs, suggesting robust IFN response generated against SARS-CoV-2 (Zhou Z. et al., 2020).
T167 28735-28955 Sentence denotes Further, a study by Ziegler et al. (2020) suggested that ACE2 may also act as a type of ISG in some respiratory epithelial cells; this may point towards using ACE2 modulators as viable therapeutic options for SARS-CoV-2.
T168 28956-29095 Sentence denotes Based on the recent clinical data on COVID-19 patients, we can infer that mild/moderate patients should possess optimal early IFN response.
T169 29096-29234 Sentence denotes Whereas, weak or delayed IFN response may be the tipping point in eliciting hyperinflammatory state, allowing extensive viral propagation.
T170 29235-29427 Sentence denotes Previous studies in animal models have shown that early IFN response was the determining factor in inhibiting viral propagation and attenuating disease condition (Channappanavar et al., 2016).
T171 29428-29577 Sentence denotes In line with this, a recent study has shown that COVID-19 patients with mild/moderate conditions possess functional type I and type III IFN response.
T172 29578-29695 Sentence denotes Specifically, patients with mild/moderate symptoms have adequate levels of IFNA transcript and protein in the plasma.
T173 29696-29915 Sentence denotes The presence of detectable IFN levels in these subsets of patients was also associated with the expression of downstream signaling receptors and molecules like IFNAR1, JAK1, and TYK2, suggesting functional IFN response.
T174 29916-30043 Sentence denotes However, no IFNB mRNA or protein was detected, while optimal levels of IFN-λ were detected both at the mRNA and protein levels.
T175 30044-30188 Sentence denotes Expectedly, the levels of type I and type III IFNs positively correlated with the viral load and severity of the disease (Hadjadj et al., 2020).
T176 30189-30436 Sentence denotes In agreement with the critical role of early IFN response in attenuating infectious state, another study finds that cells pre-treated with IFN-β or IFN-λ exhibit resistance to SARS-CoV-2 infection by significantly decreasing the virus copy number.
T177 30437-30539 Sentence denotes Similarly, 3D culture organoids pre-treated with either IFN-β or IFN-λ led to reduced viral infection.
T178 30540-30754 Sentence denotes Cells depleted for either IFNAR1 or IFNLR1 had an overall increase in the number of SARS-CoV-2 infected cells, suggesting the integral role of IFN signaling in attenuating viral propagation (Stanifer et al., 2020).
T179 30755-30923 Sentence denotes Further, IFN response was adequate in younger patients compared to older ones, which may partly explain the higher risk of infection in older people (Wei et al., 2020).
T180 30924-31197 Sentence denotes Additionally, people with comorbid conditions like diabetes – a condition associated with impaired IFN response, are more susceptible to SARS-CoV-2 infection, which further points toward the critical role of IFN signaling in the early clearance of the virus (Erener, 2020).
T181 31198-31409 Sentence denotes However, a comprehensive and longitudinal analysis of the IFN response in mild/moderate patients is warranted to understand the functional consequence of this immune response throughout the disease and recovery.
T182 31410-31707 Sentence denotes Overall, considering the relatively better IFN response and ISG expression induced by SARS-CoV-2, one can argue that this functional immune response is a probable reason for the relatively lower mortality rate seen in COVID-19, compared to previous SARS-CoV and MERS infections (Meo et al., 2020).
T183 31708-31760 Sentence denotes However, these early findings warrant further proof.
T184 31762-31819 Sentence denotes Early Immune Response by Alveolar Epithelial Cells (ATII)
T185 31820-32070 Sentence denotes Activated alveolar macrophages (AM) and recruited inflammatory monocytes/macrophages are majorly responsible for the secretion of cytokines and chemokines in early phases of infection, with a substantial contribution from infected ATII cells as well.
T186 32071-32242 Sentence denotes This early response is necessary to recruit and activate the adaptive immune system and hence drive the clearance of the virus without inflicting immunopathological state.
T187 32243-32450 Sentence denotes While the levels of cytokines and chemokines are well-regulated during this phase of infection, a check on the activation profile and recruitment of these innate immune to the sites of infection is critical.
T188 32451-32806 Sentence denotes Thus, a regulated and controlled release of cytokines and chemokines in the early phase of infection is not necessarily proinflammatory but drives the successful viral clearance and the probable reason behind the limited propagation of infection as seen in the majority of the COVID-19 cases exhibiting mild symptoms (Song et al., 2020; Tay et al., 2020).
T189 32807-33049 Sentence denotes Among the cytokines secreted by virus-infected airway epithelial cells, IL-6 plays a prominent role in the early recruitment and differentiation of monocytes, neutrophils, and lymphocytes which express the corresponding IL-6 receptor (IL-6R).
T190 33050-33202 Sentence denotes Though IL-6 is chiefly secreted by macrophages (activated AMs and inflammatory macrophages) in the lungs, secretion of IL-6 by ATII is also significant.
T191 33203-33385 Sentence denotes In vitro studies on SARS-CoV have shown the release of IL-6 by ATII in response to RIG-I and TLR signaling via activation of NF κB pathway (Ndlovu et al., 2009; Tanaka et al., 2012).
T192 33386-33565 Sentence denotes Additionally, proinflammatory cytokines TNF-α and IL-1β secreted by macrophages act on ATII cells to cause the release of IL-6 (Crestani et al., 1994; Schwingshackl et al., 2013).
T193 33566-33835 Sentence denotes Transcriptional profiling in normal human bronchial epithelial (NHBE) infected with SARS-CoV-2 shows upregulation of IL-6, suggesting that these lung epithelial cells may contribute to early IL-6 response seen in non-severe COVID-19 patients (Blanco-Melo et al., 2020).
T194 33836-34021 Sentence denotes However, more conclusive studies like tissue immunohistochemistry or single-cell immuno-profiling of the lung epithelial cells will clarify their contribution in IL-6 secretion in vivo.
T195 34023-34068 Sentence denotes Early Immune Response by Alveolar Macrophages
T196 34069-34228 Sentence denotes Lung resident macrophages like AM are generally present in the terminal airways where they serve a regulatory function to maintain normal cellular homeostasis.
T197 34229-34343 Sentence denotes Previous studies have defined a critical role of these cells in successful viral clearance (Hartwig et al., 2014).
T198 34344-34484 Sentence denotes Depletion of these cells in animals infected with mouse hepatitis virus type 1 (MHV-1) resulted in a marked reduction of antiviral response.
T199 34485-34550 Sentence denotes AMs have also been shown indispensable during SARS-CoV infection.
T200 34551-34675 Sentence denotes The depletion of these cells was associated with worsened disease outcomes in a mouse model of SARS-CoV (Page et al., 2012).
T201 34676-34876 Sentence denotes Further, BALF fluid analysis of SARS-CoV infected patients revealed an increase in AM population, which persisted over two months and significantly correlated with viral clearance (Wang et al., 2005).
T202 34877-35159 Sentence denotes In addition to their activation by the secondary response during viral infection, few in vitro studies have shown that these cells can also be directly targeted by SARS-CoV (Mossel et al., 2008; Joel Funk et al., 2012), though contradictory reports are available (Yip et al., 2014).
T203 35160-35382 Sentence denotes Overall, the data supporting the antiviral response by AMs cells is largely based on other respiratory infections like influenza virus and MERS, with a few reports on SARS-CoV (Mossel et al., 2008; Joel Funk et al., 2012).
T204 35383-35627 Sentence denotes Studying these responses in COVID-19 patients may be challenging due to technical limitations (like difficulty in obtaining the optimal number of these cells from the lungs and their rapid functional and phenotypic changes during cell culture).
T205 35628-35763 Sentence denotes However, we can draw inferences from other cell types and correlate specific markers from cells directly obtained from the lung tissue.
T206 35764-35914 Sentence denotes One such recent elegant study using scRNA-seq and cluster analysis revealed the activation status of AMs in BALF fluid derived from COVID-19 patients.
T207 35915-36075 Sentence denotes The analysis is based on the signature genes expressed by these cells, which are markedly different from recruited inflammatory macrophages (Liao et al., 2020).
T208 36076-36256 Sentence denotes Surprisingly, the number of these cells declined in patients with severe disease symptoms, and the presence of proinflammatory macrophages can take their place (Liao et al., 2020).
T209 36257-36429 Sentence denotes A recent study (pre-print, not yet peer-reviewed) has shown infection and propagation of SARS-CoV-2 in macrophages present in lymph nodes and spleen (Chen Y. et al., 2020).
T210 36430-36550 Sentence denotes However, direct infection and replication of the virus was not explored in detail, specifically under in vitro settings.
T211 36551-36670 Sentence denotes Previous studies on SARS-CoV suggest low replication in these cells, probably due to phagocytosis (Yilla et al., 2005).
T212 36671-37025 Sentence denotes Thus, these results suggest that AMs’ response to SARS-CoV-2 may be complicated but necessary for the activation and recruitment of other innate cells like monocytes, dendritic cells, neutrophils, natural killer (NK) cells, and essential in the regulation of the adaptive immune system (Soroosh et al., 2013; Hartwig et al., 2014; Meischel et al., 2020).
T213 37027-37063 Sentence denotes Dysfunctional Innate Immune Response
T214 37064-37284 Sentence denotes On average, about 15% of the COVID-19 patients exhibit severe disease symptoms whereas 5% become critical, but the figures are subject to change owing to the ongoing increase in the number of cases (Berlin et al., 2020).
T215 37285-37619 Sentence denotes By looking at the immunological trajectories of these patients, it has become evident that impaired early IFN response followed by hyperactivated innate and a dysfunctional adaptive immune response is the vital pathological factors contributing to disease severity in COVID-19 patients (Blanco-Melo et al., 2020; Mathew et al., 2020).
T216 37620-37850 Sentence denotes However, there are also reports, suggesting a more complex interplay in these immune responses, which needs a thorough understanding of developing effective immunotherapy-based interventions and for successful vaccine development.
T217 37852-37880 Sentence denotes Impaired Interferon Response
T218 37881-38565 Sentence denotes Based on previous molecular and clinical studies on SARS-CoV and the recent data on SARS-CoV-2, it is becoming evident that the delay in primary IFN response may be due to multiple factors such as (1) poor overall immune function of a patient with a compromised adaptive response as in older people, (2) patients with comorbidity, (3) genetic factors or epigenetic changes associated with crucial genes and transcriptional factors involved in IFN signaling, and (4) age and sex of the patient, probably making the older individuals and males more susceptible to COVID-19 (Bastard et al., 2020; Li M.Y. et al., 2020; Nguyen et al., 2020; Verdecchia et al., 2020; Zhou F. et al., 2020).
T219 38566-38676 Sentence denotes Thus, overall these factors may compromise the host cell immune system and delay the early antiviral response.
T220 38677-38831 Sentence denotes Especially in the case of RNA viruses, evasion of host immune response is managed by interfering with PRRs, PLRs, TLRs, and IFN signaling (Kikkert, 2020).
T221 38832-38984 Sentence denotes Additionally, inhibition is also conferred by hijacking host cell biosynthetic machinery and eventually inducing host cell apoptosis as discussed above.
T222 38985-39185 Sentence denotes Previous studies have unequivocally demonstrated poor IFN response to SARS-CoV during severe infection, which is also apparently the case with SARS-CoV-2, reviewed recently by Park and Iwasaki (2020).
T223 39186-39331 Sentence denotes In vitro culture of the primary lung, epithelial cells infected with the SARS-CoV-2 generated inadequate IFN response (Blanco-Melo et al., 2020).
T224 39332-39468 Sentence denotes By looking at the clinical samples, a large body of data suggests impaired IFN signaling in severe and critically ill COVID-19 patients.
T225 39469-39700 Sentence denotes Blood analysis from across the studies reveals low or undetectable levels of IFN-β and IFN-λ levels in patients exhibiting severe disease symptoms or patients admitted to the ICU with in a critical condition (Hadjadj et al., 2020).
T226 39701-39840 Sentence denotes Of note, an elegant study was conducted to explore the functional role of IFN signaling during various stages of COVID-19 disease severity.
T227 39841-39985 Sentence denotes The study found robust impairment of IFN signaling in critically ill and severe patients in comparison to mild/moderate and healthy individuals.
T228 39986-40178 Sentence denotes IFN-β mRNA and protein were undetectable in all patients, whereas IFN-α2 protein was highly reduced in the plasma of severe and critically ill patients, corroborated with reduced IFN activity.
T229 40179-40393 Sentence denotes In line with the impaired IFN signaling, robust downregulation of some of the ISGs (MX1, IFITM1, IFIT2) observed in severe and critically ill patients suggest an overall reduced IFN response (Hadjadj et al., 2020).
T230 40394-40587 Sentence denotes Consistent with the low circulating levels of IFNs, transcriptional analysis of post-mortem lung samples further confirmed these observations and revealed no detectable type I or Type III IFNs.
T231 40588-40745 Sentence denotes Among the SARS-CoV-2 proteins which directly interfere with IFN response, ORF6, ORF8, and N protein inhibit IFN-β and NF-κB signaling (Li J.Y. et al., 2020).
T232 40746-40872 Sentence denotes Further, Konno et al. (2020) have identified a more extended variant of ORF3b with presumably more vigorous anti-IFN activity.
T233 40873-40989 Sentence denotes Thus, these early observations may point towards an impaired early IFN response by the host cells against SARS-CoV-2
T234 40990-41150 Sentence denotes Adding to the essential role of IFN in early antiviral response, two recent studies have shown that genetic changes are associated with inadequate IFN response.
T235 41151-41305 Sentence denotes In the first study, the presence of IFN neutralizing auto-antibodies found in patients who exhibited more severe disease condition (Bastard et al., 2020).
T236 41306-41426 Sentence denotes These auto-antibodies were more prevalent in men than women, that partly explains the susceptibility of men to COVID-19.
T237 41427-41497 Sentence denotes None of the asymptomatic or mild cases had detectable auto-antibodies.
T238 41498-41632 Sentence denotes In the other study, mutations in 13 key genes implicated in TLR3- and IRF7-dependent exhibit loss-of-function (Zhang Q. et al., 2020).
T239 41633-41787 Sentence denotes Patients or the cells derived from these patients with loss-of-function in these genes had inadequate IFN response and vulnerable to SARS-CoV-2 infection.
T240 41788-41963 Sentence denotes In a similar study on four patients with severe disease symptoms, the whole exome-sequencing revealed loss-of-function of TLR7, which is essentially involved in IFN signaling.
T241 41964-42104 Sentence denotes These patients exhibited decreased expression of IRF7, IFNB1, and ISG15, along with reduced production of IFN-γ (Van Der Made et al., 2020).
T242 42105-42431 Sentence denotes Thus, impaired IFN signaling, mediated either directly by the virus by interfering at various steps in the IFN signaling, or genetic predisposition of some individuals to inadequate IFN response and presence of IFN neutralizing auto-antibodies are some of the significant factors which determine the COVID-19 disease severity.
T243 42432-42636 Sentence denotes The dysfunctional IFN response in conjunction with other innate and adaptive immune responses may thus decide the path to recovery or progression to more severe form of the disease (Hadjadj et al., 2020).
T244 42637-42787 Sentence denotes Impaired type I interferon activity and exacerbated inflammatory responses in severe COVID-19 patients (Hadjadj et al., 2020; Park and Iwasaki, 2020).
T245 42788-42963 Sentence denotes A comprehensive understanding of the molecular mechanisms by which SARS-CoV-2 causes impaired IFN response is still lacking, and future studies may help us to understand this.
T246 42964-43142 Sentence denotes Nevertheless, these initial reports, along with the previous findings on SARS-CoV, are the basis behind exploring the therapeutic efficacy of IFN treatment for COVID-19 patients.
T247 43143-43292 Sentence denotes Currently, there are ongoing clinical trials with IFN-β1a (NCT04350671), which is in phase II, and IFN-l (NCT04388709) for the treatment of COVID-19.
T248 43293-43398 Sentence denotes The preliminary results with these drugs have been encouraging as of now (Davoudi-Monfared et al., 2020).
T249 43400-43477 Sentence denotes Release of Damage-Associated Molecular Patterns and Proinflammatory Molecules
T250 43478-43646 Sentence denotes The impaired early IFN response results in high viral propagation that subsequently leads to the induction of a robust proinflammatory response (Davidson et al., 2015).
T251 43647-43882 Sentence denotes The cytopathic nature of these viruses induces substantial death in infected ATII cells (apoptotic as well as necrotic) which leads to the release of a wide range of damage-associated molecular patterns (DAMPs) and cytotoxic molecules.
T252 43883-44015 Sentence denotes Similarly, activated AMs also respond to the released DAMPs and act concurrently with PAMPs to amplify the proinflammatory response.
T253 44016-44143 Sentence denotes A list and role of potential PAMPs, DAMPs, and their respective PRRs have been reviewed previously (Leiva-Juárez et al., 2018).
T254 44144-44249 Sentence denotes Circulating nuclear and mitochondrial DNA, and histones serve as potential DAMPs during viral infections.
T255 44250-44351 Sentence denotes These molecules signal via the TLR pathway and induce robust expression of proinflammatory molecules.
T256 44352-44552 Sentence denotes Among the DAMPs secreted by virus-infected and damaged epithelial cells, the role of high-mobility group box one protein (HMGB1) and S100 are well known (Leiva-Juárez et al., 2018; Gong et al., 2020).
T257 44553-44660 Sentence denotes HMGB1 after binding to TLR4 induces activation of NF-κB signaling and release of proinflammatory molecules.
T258 44661-44845 Sentence denotes Additionally, HMGB1 also activates receptors like TREM1/2, and receptors for advanced glycation end products (RAGE) which are also involved in NF-κB activation (Yang and Tracey, 2010).
T259 44846-45011 Sentence denotes S100 initiates similar downstream signaling after binding with TLR4 and RAGE receptors (Ma et al., 2017), these studies were recently reviewed by Gong et al. (2020).
T260 45012-45189 Sentence denotes Previous animal studies with other respiratory viruses have shown a close correlation of increased serum HMGB1 levels with lung injury and disease severity (Patel et al., 2018).
T261 45190-45352 Sentence denotes Similarly, elevated expression of S100A9 was present in patients during acute lung injury mediated by the respiratory syncytial viral (RSV; Foronjy et al., 2016).
T262 45353-45645 Sentence denotes Although as of now, presence of HMGB1 has no report in COVID-19 patients, the damage in the lung parenchyma in post-mortem biopsies suggests that it is highly likely that this protein may implicate in disease pathogenesis and hyperinflammation (Andersson et al., 2020; Zhang Q. et al., 2020).
T263 45646-45855 Sentence denotes Increased expressions of S100A8, S100A9, and S100A12 calgranulins found in the BALF fluid from COVID-19 patients indicate their potential role in generating the proinflammatory response (Zhou Z. et al., 2020).
T264 45856-46005 Sentence denotes Further, Zou et al. (2020) showed increased presence of cell-free DNA and citrullinated histones in blood samples obtained from 50 COVID-19 patients.
T265 46006-46164 Sentence denotes Studies on other inflammatory diseases have shown a close correlation between the presence of these molecules with disease severity (Resman Rus et al., 2016).
T266 46165-46349 Sentence denotes However, their functional role is yet unexplored, but the increased expression of some of these DAMPs in COVID-19 patients suggests their potential implication in disease pathogenesis.
T267 46350-46495 Sentence denotes Future studies will clarify the involvement of various other DAMPs in perpetuating the proinflammatory state, and specifically the role of HMGB1.
T268 46496-46660 Sentence denotes In addition to the secretion of DAMPs, AM and virus infected ATII cells secrete a range of pro-inflammatory molecules (Hussell and Bell, 2014; Glaser et al., 2019).
T269 46661-46859 Sentence denotes Among these, increased IL-6 levels are consistently detected in cultured cells infected with SARS-CoV and SARS-CoV-2 (Ye et al., 2018; Herold et al., 2020; Liu J. et al., 2020; Liu T. et al., 2020).
T270 46860-47118 Sentence denotes Notably, levels of TNF-α, IL-8, IL-10, GM-CSF, CXCL10, and CCL5 secreted by infected ATII and activated AMs were also consistently shown to increase during SARS-CoV and SARS-CoV-2 infections (Ward et al., 2005; Huang C. et al., 2020; Patterson et al., 2020).
T271 47119-47441 Sentence denotes Transcriptional profiling of cytokines and chemokines in normal human lung epithelial cells (NHBE) infected with SARS-CoV-2 revealed increased levels of CCL20, CXCL1, IL-1B, IL-6, CXCL3, CXCL5, CXCL6, CXCL2, CXCL16, and TNF-α by primary lung epithelial cells in response to SARS-CoV-2 infection (Blanco-Melo et al., 2020).
T272 47442-47593 Sentence denotes Thus, lung resident ATII and AM cells besides being integral to the antiviral response also participate in generating a profound proinflammatory state.
T273 47595-47659 Sentence denotes Proinflammatory Molecules Released by Infiltrating Myeloid Cells
T274 47661-47707 Sentence denotes Circulating inflammatory monocytes/macrophages
T275 47708-47831 Sentence denotes A detailed account of the role of inflammatory macrophages in the pathogenesis of SARS-CoV is reported by He et al. (2007).
T276 47832-48061 Sentence denotes Animal studies have demonstrated extensive recruitment and accumulation of these cells in the lungs, which correlated with the release of TNF-α, IL-1β, and IL-6 and the development of ARDS, reviewed by Gralinski and Baric (2015).
T277 48062-48287 Sentence denotes Interestingly, depletion of these inflammatory macrophages in animals infected with SARS-CoV was associated with a high recovery rate, thus suggesting their critical role in disease pathogenesis (Channappanavar et al., 2016).
T278 48288-48469 Sentence denotes Similarly, SARS-CoV infection in animals with STAT1 knockout in alternatively activated macrophages displayed attenuated lung damage and protection from disease (Page et al., 2012).
T279 48470-48638 Sentence denotes Besides, a large number of clinical studies support an integral role of IMMs in SARS-CoV infected patients (Wong et al., 2004; Tisoncik et al., 2012; Liu et al., 2019).
T280 48639-48844 Sentence denotes Recent studies from BALF from COVID-19 patients have also demonstrated the critical role of circulating monocyte-derived macrophages in the induction of robust proinflammatory reaction (Liao et al., 2020).
T281 48845-48970 Sentence denotes Blood cell analysis of 18 COVID-19 patients revealed an activated status of inflammatory macrophages (Zhang D. et al., 2020).
T282 48971-49127 Sentence denotes In line with these findings, scRNA-seq followed by immune cell profiling of blood cells revealed an increased number of CD14++ monocytes (Wen et al., 2020).
T283 49128-49265 Sentence denotes Severe and critically ill patients also exhibit macrophage activation syndrome (MAS) in some cases (Giamarellos-Bourboulis et al., 2020).
T284 49266-49420 Sentence denotes Thus, all the evidence directs towards a critical role of inflammatory macrophages in disease severity during COVID-19 and a potential therapeutic target.
T285 49421-49597 Sentence denotes Intervention which reduces the impetus to induce MAS like antibodies directed against IL-6 and IL-1β has shown promising clinical outcomes, reviewed by Otsuka and Seino (2020).
T286 49599-49626 Sentence denotes Proinflammatory neutrophils
T287 49627-49856 Sentence denotes Like other innate immune cells, neutrophils are protective in the early phases of infection by neutralizing the viral particles and release of protective molecules to interfere with the viral propagation (Drescher and Bai, 2013).
T288 49857-49994 Sentence denotes However, in severe cases, the number of these cells increases at the sites of infection and they become the leading damage-causing cells.
T289 49995-50245 Sentence denotes Excessive infiltration of these cells in the lungs is associated with secretion of TNF-α, IL-6, IL-1β, IL-7, IL-23, and IL-36, along with a broad range of other cytokines and damage-causing neutrophil extracellular traps (NETs; Tecchio et al., 2014).
T290 50246-50425 Sentence denotes Additionally, these neutrophils also secrete a range of chemokines like CCL2/3/4, CXCL1-13 to attract more neutrophils and monocytes from the circulation (Sokol and Luster, 2015).
T291 50426-50515 Sentence denotes Emerging evidence suggests a pivotal role of neutrophils in the pathogenesis of COVID-19.
T292 50516-50730 Sentence denotes Immune cell profiling revealed activated status of these cells which was associated with increased levels of NETs and correlated with acute-phase reaction (Chen G. et al., 2020; Qin et al., 2020; Zuo et al., 2020).
T293 50731-50878 Sentence denotes Similarly, an increase in the number of activated neutrophils was present in the BALF of COVID-19 patients (Liao et al., 2020; Xiong et al., 2020).
T294 50879-51041 Sentence denotes Thus, based on these recently published studies, the neutrophil number in the blood can be used as a predictive marker for disease severity (Zhang et al., 2020a).
T295 51043-51063 Sentence denotes Natural killer cells
T296 51064-51266 Sentence denotes Natural killer cells are essential in the early phase of viral infection to assist in the clearance of the virus by interacting with death receptors expressed on the infected cells (Vidal et al., 2011).
T297 51267-51414 Sentence denotes Previous clinical studies have shown decreased NK cell number in SARS-CoV patients, which was more pronounced in severe cases (Wang and Xia, 2004).
T298 51415-51657 Sentence denotes A recent blood profile of COVID-19 patients suggested a similar decline in the number of NK cells in severe cases, along with an increased expression of exhaustion markers (Chen X. et al., 2020; Tan L. et al., 2020b; Zheng H.Y. et al., 2020).
T299 51658-51804 Sentence denotes On the contrary, no significant difference was found in the number of total NK cells, in non-ICU vs 10 ICU admitted patients (Zhou et al., 2020a).
T300 51805-51961 Sentence denotes This discrepancy in number could probably be due to differential temporal immune response and the underlying prevailing disease conditions in some patients.
T301 51962-52190 Sentence denotes Immune cell profiling data from early recovery stage (ERS) and late recovery stage (LRS) COVID-19 patients revealed a biphasic effect, with fewer NK cells during early recovery ERS, which recovered during LRS (Wen et al., 2020).
T302 52191-52363 Sentence denotes Thus, besides the underlying disease state, the NK cell number may also be sensitive to the time of sample collection and hence may not serve as a potential disease marker.
T303 52364-52654 Sentence denotes Further, these studies could also suffer from the limitation of the variation in the age of the patients studied which may make it difficult to provide a definite role of these cells concerning COVID-19 disease severity (Nikolich-Zugich et al., 2020), necessitating more conclusive studies.
T304 52656-52706 Sentence denotes Lung resident and monocyte-derived dendritic cells
T305 52707-52854 Sentence denotes Lung resident dendritic cells majorly have a protective role during the early onset of the disease by activating the adaptive immune cell response.
T306 52855-53129 Sentence denotes Under the influence of PAMPs, DAMPs, and inflammatory cytokine signaling, lung resident dendritic cells are conditioned and migrate to the draining lymph node under the influence of CCR7 where they prime naïve CD4+ and CD8+ T cells (Braun et al., 2011; Thaiss et al., 2011).
T307 53130-53292 Sentence denotes In contrast, monocyte-derived dendritic cells generate under the influence of GM-CSF, IFN-γ, and IL-4, along with other proinflammatory signals (Qu et al., 2014).
T308 53293-53477 Sentence denotes Previous studies have shown elevated secretions of CCL3, CCL5, MCP-1, IP-10, TNF-α, and IL-6 by activated inflammatory dendritic cells (DCs) in response to SARS-CoV (Law et al., 2005).
T309 53478-53569 Sentence denotes Recent reports also suggest the presence of activated dendritic cells in COVID-19 patients.
T310 53570-53821 Sentence denotes Notably, meta-transcriptomic sequencing of BALF obtained from 8 COVID-19 patients revealed an activated status of these cells along with neutrophils, as compared to other innate and adaptive immune cells (Yang A.P. et al., 2020; Zhou Z. et al., 2020).
T311 53822-54247 Sentence denotes Thus, based on previous clinical studies on SARS-CoV infection and recent emerging studies on SARS-CoV-2, it is evident that hyperinflammatory immune response in severe and critically ill COVID-19 patients is mainly mounted by infiltrated innate immune cells at the site of infection with a substantial contribution by the adaptive immune cells as discussed below in the section on the dysfunctional adaptive immune response.
T312 54249-54285 Sentence denotes Adaptive Immune Response in COVID-19
T313 54287-54322 Sentence denotes Functional Adaptive Immune Response
T314 54323-54427 Sentence denotes The functional but well-regulated adaptive immune response is necessary to overcome the viral infection.
T315 54428-54672 Sentence denotes Specifically, T cells when recruited to the site of infection engage in eliminating the infected cells and act in concordance with virus-specific neutralization antibodies to provide sustained immunity (Hor et al., 2015; De Biasi et al., 2020).
T316 54673-54999 Sentence denotes Considering the recent extensive work in understanding the functional early immune response during COVID-19, it appears that a complex interplay between T and B cell immune response along with patient-specific underlying health condition and genetic factors determines the recovery, as will be discussed in following sections.
T317 55001-55016 Sentence denotes T Cell Response
T318 55017-55230 Sentence denotes Generation of early adaptive immune response is critical for the selective elimination of virus-infected cells and neutralization of viral antigens, thereby preventing the damage to the underlying lung parenchyma.
T319 55231-55436 Sentence denotes Cytokines, chemokines, PAMPs, and DAMPs released by infected ATII and activated AMs in the lung are adequate to mount a well-coordinated and regulated adaptive immune response by priming lung resident DCs.
T320 55437-55555 Sentence denotes After encountering the antigen-presenting DCs, naive CD4+ T cells differentiate into effector and memory CD4+ T cells.
T321 55556-55778 Sentence denotes At least five different CD4+ T cell lineages are known (TH1, TH2, TH17, TFH, and TREG cells) with prominent roles of TH1 and TFH cells in mounting antiviral response during SARS-CoV infection (Channappanavar et al., 2014).
T322 55779-55888 Sentence denotes Additionally, some studies have also shown a functional TH2 response in PBMCs derived from COVID-19 patients.
T323 55889-56022 Sentence denotes Release of TH2 specific cytokines like IL-4 and IL-5 was observed in vitro after these cells were stimulated (Weiskopf et al., 2020).
T324 56023-56170 Sentence denotes Similarly, these patients show enhanced production of IL-17 along with other TH17 cell-specific cytokines (Liu J. et al., 2020; Wu and Yang, 2020).
T325 56171-56377 Sentence denotes These findings suggest that the TH cell response in COVID-19 patients is complex concerning other infections, and this complexity may partly depend upon the prevailing pathophysiological state of a patient.
T326 56378-56542 Sentence denotes During viral infections like SARS-CoV, TH1 differentiation is influenced by IL-12 and IFN-γ secreted by DCs along with co-stimulatory signaling via B7-1/2 and CD28.
T327 56543-56680 Sentence denotes Whereas IL-6 secreted by DCs influence TFH differentiation to aid in antibody secretion by B cells (Tang et al., 2008; Lau et al., 2012).
T328 56681-56938 Sentence denotes Under the influence of chemokines (CCL3, CCL4, CCL5, CCL8), TH1 cells are recruited to the site of infection and are distinguished by the secretion of IL-2, IFN-γ, IL-12, and TNF-α as the main effector cytokines during SARS-CoV infections (Li et al., 2008).
T329 56939-57110 Sentence denotes Similarly, naive CD8+ T cells are activated by DCs by engaging MHC-I and TCR receptors, along with CD28-B7 co-stimulatory signaling and cytokines released by CD4+ T cells.
T330 57111-57259 Sentence denotes IL-2 secreted chiefly by CD4+ T cells is also implicated in their long-term maintenance and proliferation (Eickhoff et al., 2015; Hor et al., 2015).
T331 57260-57436 Sentence denotes Notably, CD8+ T cells could also be activated independently of help from CD4+ T cells under conditions where a robust IFN Type I response is present (Wiesel and Oxenius, 2012).
T332 57437-57653 Sentence denotes These activated CD8+ T cells [also referred to as cytotoxic T lymphocytes (CTLs)] get subsequently recruited to the effector organ under the influence of chemokines (CCL3, CCL4, CCL5, CXCL9, and CXCL10) (Nolz, 2015).
T333 57654-57853 Sentence denotes At the infected site, CTLs mount an antiviral response by directly killing the infected cells via secretion of cytotoxic molecules like granzymes, perforins, granulysin, and other cytotoxic granules.
T334 57854-58101 Sentence denotes Very recently, a study shows that CTLs secrete the granzymes and perforins as supramolecular attack particles (SMAPs) in a glycoprotein complex along with over 283 other proteins (including cytokines such as IFN-γ and TNF-α) (Bálint et al., 2020).
T335 58102-58203 Sentence denotes It will be interesting to know whether infection by CoVs also influences the release of SMAP by CTLs.
T336 58204-58345 Sentence denotes Animal studies have revealed the critical molecular insights of CD4+ cells in SARS-CoV clearance and attenuation of a pathological condition.
T337 58346-58485 Sentence denotes The depletion of CD4+ cells was associated with reduced virus clearance and interstitial pneumonitis (Jin et al., 2005; Wang et al., 2006).
T338 58486-58611 Sentence denotes In comparison, the adoptive transfer of virus-specific CD4+ and CD8+ T cells resulted in viral clearance (Zhao et al., 2010).
T339 58612-58828 Sentence denotes Similarly, clinical data has consistently shown the presence of antigen-specific CD4+ and CD8+ T cells in the recovered patients, akin to what was found in immunized animals, reviewed in Channappanavar et al. (2014).
T340 58829-58965 Sentence denotes On the other hand, severe cases of SARS-CoV infection were associated with a decline in T cells, as will be discussed in later sections.
T341 58966-59139 Sentence denotes Thus, based on these animal and clinical data, CD4+ T and CD8+ T cells were central to the antiviral response during SARS-CoV infection (Peng et al., 2006; Oh et al., 2012).
T342 59140-59255 Sentence denotes A subset of primed CD4+ and CD8+ T cells differentiates into long-acting memory cells after the infection subsides.
T343 59256-59429 Sentence denotes TCR-p: MHCII signaling helps in CD4+ T memory cell formation along with presence of cytokines like IL-2, IL-21 and interaction via CD40R-CD40L (Jaigirdar and MacLeod, 2015).
T344 59430-59577 Sentence denotes Similarly, This CD8+ T cell transition to memory cells take place under the influence of CD8+ TREG cells via secreted IL-10 (Laidlaw et al., 2015).
T345 59578-59715 Sentence denotes Long lasting CD4+ and CD8+ T memory cells were detected in the recovered SARS-CoV infected patients (Peng et al., 2006; Li et al., 2008).
T346 59716-59876 Sentence denotes Besides, other T cells subsets which are involved in antiviral response include unconventional NKT cells (CD56+) and MAIT (mucosa-associated invariant T) cells.
T347 59877-60046 Sentence denotes NKT cells act at the interface between innate and adaptive immune response and traffic to the site of infection under the influence of cytokines (Tsay and Zouali, 2018).
T348 60047-60155 Sentence denotes MAIT cells reside in the mucosal lining, such as in the lungs where they serve an immunoregulatory function.
T349 60156-60298 Sentence denotes Both these cell types play an essential role in the early clearance of the SARS-CoV-2, along with other T cell subsets (Grifoni et al., 2020).
T350 60299-60409 Sentence denotes Strategies to enhance their function are proposed to enhance the virial clearance during COVID-19 (Cao, 2020).
T351 60410-60580 Sentence denotes Role of these cells will be further discussed under the dysfunctional immune response in section “T and B Cell Response in Mild/Moderate and Recovered COVID-19 Patients.”
T352 60582-60597 Sentence denotes B Cell Response
T353 60598-60686 Sentence denotes B cells, along with T cells, form the central adaptive response during viral infections.
T354 60687-60817 Sentence denotes B cell response is highly specific, mounted by the virus-specific antibodies and other effector cytokines secreted by these cells.
T355 60818-60999 Sentence denotes B cell activation can be follicular helper T (TFH) cell-dependent, or in some instances, independent of helper cells; both instances are prevalent in COVID-19 (Mathew et al., 2020).
T356 61000-61283 Sentence denotes Under the influence of antigen-presenting dendritic cells, naïve CD4+ T cells differentiate into TFH cells, which are marked by high expressions of CXCR5 and IL-21, and low expressions of CCR7, IFN-γ, IL-4, and IL-17 (Rasheed et al., 2006; Nurieva et al., 2008; Morita et al., 2011).
T357 61284-61477 Sentence denotes The activated TFH cells interact with B cells via CD40R-CD40L and other associated receptors to induce the production of antigen-specific antibodies in a well-coordinated and regulated process.
T358 61478-61706 Sentence denotes This CD40R-CD40L interaction along with the secretion of IL-21 also allows the formation of long-lived memory B cells, while B cell-derived IL-6 and IL-27 help in reciprocal maintenance of TFH cells (Nurieva et al., 2008, 2009).
T359 61707-61871 Sentence denotes A previous animal study has shown the essential role of these helper cells in mounting an adequate antibody response against SARS-CoV infection (Chen et al., 2010).
T360 61872-61980 Sentence denotes The depletion of these cells was associated with a decline in antibody response and reduced viral clearance.
T361 61981-62099 Sentence denotes Thus, virus-specific antibodies produced by B cells are critical for an effective immune response mounted by the host.
T362 62100-62304 Sentence denotes These antibodies facilitate the clearance of the virus by either directly activating phagocytosis, opsonization, or activation of the antibody-dependent cellular cytotoxicity (ADCC) via effector NK cells.
T363 62305-62416 Sentence denotes Cytokines released by the activation of innate and adaptive immune systems also activate the complement system.
T364 62417-62566 Sentence denotes Viruses coated with the secreted antibodies from plasma cells eventually get eliminated by the complement system, reviewed by Risitano et al. (2020).
T365 62568-62638 Sentence denotes T and B Cell Response in Mild/Moderate and Recovered COVID-19 Patients
T366 62639-62784 Sentence denotes T cell response is an emerging critical determinant in keeping the SARS-CoV-2 infection under check (Huang C. et al., 2020; Liu J. et al., 2020).
T367 62785-63156 Sentence denotes Across studies, a decline in the number of these cells positively correlates with poor clinical outcome and immuno-pathogenesis, whereas adequate T cell number and proper effector function are prevalent in patients who develop mild disease symptoms or those who successfully recovered (Chen G. et al., 2020; Li H. et al., 2020; Sekine et al., 2020; Tan L. et al., 2020b).
T368 63157-63424 Sentence denotes Following a single patient (47-year-old woman) throughout the disease, Thevarajan et al. (2020) showed a concomitant increase in CD4+, CD8+, TFH cells, and antibody-secreting B cells from day seven after infection, which persisted for a week as the symptoms resolved.
T369 63425-63630 Sentence denotes Other studies revealed a similar trend of revival in T cell response in patients who have successfully cleared the virus (Anft et al., 2020; Braun et al., 2020; Chen X. et al., 2020; Chen N. et al., 2020).
T370 63631-63760 Sentence denotes SARS-CoV-2 specific reactive CD4+ and CD8+ T cells were found in 100 and 80% patients who needed mechanical ventilation (n = 10).
T371 63761-63849 Sentence denotes PBMCs derived from these patients showed reactivity against the S protein of SARS-CoV-2.
T372 63850-64045 Sentence denotes Further, in vitro stimulation of CD4+ T cells led to their differentiation into TH1, TH2, and TH17 subsets, as revealed by the expression of their corresponding cytokines (Weiskopf et al., 2020).
T373 64046-64130 Sentence denotes Interestingly, 20% of non-infected healthy controls also displayed reactive T cells.
T374 64131-64282 Sentence denotes The main limitation with this study was that the T response was studied only in critically ill patients and the small sample size was small to provide.
T375 64283-64460 Sentence denotes By studying a cohort of 18 COVID-19 patients and 64 healthy donors, Braun et al. (2020) found reactive CD4+ (83%) cells in blood-derived from the convalescing COVID-19 patients.
T376 64461-64530 Sentence denotes These reactive T cells were found specifically against the S protein.
T377 64531-64724 Sentence denotes Interestingly about 35% of SARS-CoV-2 seronegative healthy donors also showed the presence of S protein reactive CD4+ T cells indicating previous exposure to the related coronavirus infections.
T378 64725-64879 Sentence denotes Simultaneously, another study has found SARS-CoV-2 specific CD4+ T (100%) and CD8+ T (70%) cells in convalescent patients (n = 20) (Grifoni et al., 2020).
T379 64880-65085 Sentence denotes In addition to being majorly reactive against S protein, the study found additional targets of these T cells in the form of M, N, and ORF8 proteins and other non-structural proteins like NSP3, NSP4, ORF3a.
T380 65086-65313 Sentence denotes Further, in line with the study by Braun et al. (2020), T cells were found reactive against 40–60% of the SARS-CoV-2 uninfected patients, suggesting the presence of these reactive cells in response to previous viral infections.
T381 65314-65490 Sentence denotes In a yet to be a peer-reviewed article, Schulien et al. (2020) has extensively studied the SARS-CoV-2 epitope-specific role of CD8+ T cells in COVID-19 (Schulien et al., 2020).
T382 65491-65674 Sentence denotes The study found the presence of newly generated and pre-existing SARS-CoV-2 specific cells with the positive response seen in 88.4% of patients who had mild disease symptoms (n = 26).
T383 65675-65743 Sentence denotes The most substantial response was found against N protein and ORF3a.
T384 65744-65844 Sentence denotes Further, CD8+ T cells response was shown persistent even in the individuals who became seronegative.
T385 65845-65952 Sentence denotes In a patient studied longitudinally (70 days), CD8+ T cell response prolonged but antibody did not persist.
T386 65953-66205 Sentence denotes All these three studies taken together point toward the presence of functional and long-lasting reactive T cells in convalescent individuals, while others also suggest the presence of reactive T cells in critically ill patients (Weiskopf et al., 2020).
T387 66206-66382 Sentence denotes Thus, based on these studies, it appears that COVID-19 patients who exhibit mild disease symptoms and successfully recover, display functional and long-lasting T cell response.
T388 66383-66573 Sentence denotes However, these findings may not be definitive to provide a coherent functional view of these cells during recovery, as none of these studies compared the T cell response to disease severity.
T389 66574-66661 Sentence denotes A further difference in the time of sample collection may also complicate the findings.
T390 66662-66852 Sentence denotes In the study by Grifoni et al. (2020) samples were collected throughout 20–35 days after symptom onset, whereas Weiskopf et al. (2020), used samples collected after 14 days of ICU admission.
T391 66853-66943 Sentence denotes Thus, more studies under controlled clinical settings and large cohort size are warranted.
T392 66944-67107 Sentence denotes While addressing some of these concerns, a recent study explored T cell response in convalescent COVID-19 patients concerning disease severity (Peng et al., 2020).
T393 67108-67290 Sentence denotes The study found robust CD4+ and CD8+ memory T cell response in severe cases (n = 14) than mild (n = 28), suggesting long-lasting memory of these cells to keep the infection in check.
T394 67291-67342 Sentence denotes The limitation again here is the small sample size.
T395 67343-67489 Sentence denotes Therefore, more such studies with large sample size are needed to fully understand the impact of T cell response and its long-term sustainability.
T396 67490-67648 Sentence denotes B cell response has a temporal dynamic to human infecting CoVs, with a median time of detection for SARS-CoV as 14 days, reviewed by Huang A.T. et al. (2020).
T397 67649-67906 Sentence denotes The peak antibody titer for IgG and IgM, and detection time of neutralizing antibody varied across studies with a lower time point of seroconversion for IgG, IgM, and IgA as 15 days (Hsueh et al., 2004; Mo et al., 2006; Cao et al., 2007; Yang et al., 2009).
T398 67907-67994 Sentence denotes A more dynamic range of seroconversion was observed in sera from the COVID-19 patients.
T399 67995-68176 Sentence denotes A study by Liu X. et al. (2020) on 32 patients with varying disease severity has shown detectable IgM antibodies from day four and peaked at day 20, since the onset of the symptoms.
T400 68177-68253 Sentence denotes At the same time, IgG antibodies appeared after day 7 with a peak on day 25.
T401 68254-68374 Sentence denotes When compared to the disease severity, mild cases had peak IgM response earlier than in severe cases (day 17 vs day 21).
T402 68375-68507 Sentence denotes Further, severe cases exhibited more robust IgG antibody response than mild cases, as will be discussed in the subsequent section C.
T403 68508-68785 Sentence denotes In terms of the antibody response seen after symptom onset, a similar trend was shown by Liu X. et al. (2020) who detected IgM antibodies in SARS-CoV-2 infected patients between 3 and 6 days and IgG antibodies after day 8 of symptom onset, irrespective of the disease severity.
T404 68786-68919 Sentence denotes A study by Zhou P. et al. (2020) also found mean times of IgM, IgG, and neutralizing antibodies at 12, 14, and 11 days, respectively.
T405 68920-69057 Sentence denotes These reports were consistent with the reports from Wu et al. (2020) in which neutralizing antibodies were detected starting from day 10.
T406 69058-69258 Sentence denotes An elaborate antibody profile of 285 COVID-19 patients revealed 100% IgG and 94.1% IgM antibody response with a peak around the 3rd and 4th week after symptom onset, respectively (Long et al., 2020a).
T407 69259-69543 Sentence denotes Thus, for a successful viral clearance, an adequate adaptive immune response is generated around 2nd week after symptom onset and peaks around the 3rd week for IgM and at the beginning of 4th week for IgG (Ni et al., 2020; Thevarajan et al., 2020; Wu et al., 2020; Zhao et al., 2020).
T408 69544-69848 Sentence denotes Based on these and several other studies, it is evident that the antibody response is very dynamic in COVID-19 which may be dependent on the age, sex, genetic factors, underlying disease condition and most importantly, the type of assay used for serological testing (Guan et al., 2020; Hou et al., 2020).
T409 69849-70104 Sentence denotes Overall, these initial reports unequivocally suggest an integral role of the regulated adaptive immune response in the early clearance of virus and thereby attenuation of the disease condition in almost 80% of the patients who show mild/moderate symptoms.
T410 70105-70291 Sentence denotes On the other hand, in the rest, 20% severe and critically ill patients, disease symptoms positively correlate with the degree of lymphocytopenia, as will be discussed later in section C.
T411 70292-70393 Sentence denotes A schematic representation of the functional immune response during COVID-19 is depicted in Figure 3.
T412 70394-70472 Sentence denotes FIGURE 3 Clearance of virus infected cells by engaging adaptive immune cells.
T413 70473-70583 Sentence denotes Virus infected ATII cells activate the neighboring lung resident AMs by minimizing the CD200-200L interaction.
T414 70584-70693 Sentence denotes Additional requisite activation signals are provided by DAMPs, viral derived PAMPs, and cytokines like IFN-γ.
T415 70694-70987 Sentence denotes Activated AMs along with infected ATII derived molecules activate and recruit other innate immune cells, like circulating monocytes, dendritic cells, NK cells, and neutrophils which act in a coordinated manner to eventually recruit the adaptive effector immune cells like CTLs and CD4+T cells.
T416 70988-71124 Sentence denotes These adaptive immune cells then specifically eliminate virus infected cells while minimizing the damage to the nearby uninfected cells.
T417 71125-71308 Sentence denotes Thus, a well-coordinated and regulated adaptive immune response with help from innate immune cells is critical for initial antiviral response to limit the further spread of the virus.
T418 71309-71503 Sentence denotes Green arrows indicate the cytokines released by the respective activated immune cells which activate other immune cells as well as mount an antiviral response by acting on lung epithelial cells.
T419 71504-71683 Sentence denotes An immunological enigma still eluding researchers worldwide is how the majority of COVID-19 patients remain asymptomatic, and even some with high viral load (Lee S. et al., 2020).
T420 71684-71808 Sentence denotes This dilemma can be partly explained based on the effective functional early immune response generated by the T and B cells.
T421 71809-71951 Sentence denotes Mathew et al. (2020) used a multidimensional immunoprobing study and functionally characterized clinical features with immunological features.
T422 71952-72036 Sentence denotes This study defined three immunotypes based on 50 clinical and 200 immune parameters.
T423 72037-72270 Sentence denotes The immunotype 1 was positively associated with disease severity and had hyperactivated CD4+ and CD8+ T cells, with concomitant expression of exhaustion markers, indicating robust activation followed by the exhaustion of these cells.
T424 72271-72536 Sentence denotes This immunotype may thus be vulnerable to cytokine storm, as discussed later in section “Cytokine Storm in COVID-19 Patients.” Immunotype 2 was associated with the presence of proliferating memory B cells with the optimal activation status of CD4+ and CD8+ T cells.
T425 72537-72593 Sentence denotes This immunotype did not associate with disease severity.
T426 72594-72730 Sentence denotes The immunotype 3 had no activation status of CD4+ and CD8+ T cells, and thus exhibited an inverse correlation with the disease severity.
T427 72731-72914 Sentence denotes Overall, this study addressed some of the above questions that suggested that the presence of a regulated and functional adaptive immune response is key to preventing immunopathology.
T428 72915-73053 Sentence denotes In a similar study, the activation status of T cells associated with disease severity (acute, moderate, and severe) (Sekine et al., 2020).
T429 73054-73178 Sentence denotes The activation status of these T cells correlated with the presence of SARS-CoV-2 specific IgG antibodies in these patients.
T430 73179-73467 Sentence denotes Interestingly, T cells derived from convalescent mild and asymptomatic patients exhibited functional status when stimulated in vitro with SARS-CoV-2 specific antigens, suggesting the presence of well-regulated and functional T cell response in mild and asymptomatic convalescent patients.
T431 73468-73670 Sentence denotes Thus, in patients with high viral load, an immunopathological state can be prevented if the adequate and regulated adaptive immune response is present in association with the proper interferon response.
T432 73671-73958 Sentence denotes While in patients with compromised immune response, like in comorbid conditions, even a low viral load is sufficient to induce immunopathological changes, due to either ineffective immune response or uncontrolled hyper-activated response, as will be discussed in the subsequent sections.
T433 73960-73998 Sentence denotes Dysfunctional Adaptive Immune Response
T434 73999-74073 Sentence denotes A subset of COVID-19 patients displays robust activation of T and B cells.
T435 74074-74239 Sentence denotes These exaggerated T cell responses are specifically present in patients who manifest severe disease conditions and need mechanical ventilation (Herold et al., 2020).
T436 74240-74474 Sentence denotes Further, analysis of peripheral blood, BALF, and post-mortem lung samples of deceased patients reveal robust activation of T and B cells with a concomitant decline in the number of these cells (Kaneko et al., 2020; Liao et al., 2020).
T437 74475-74657 Sentence denotes Thus, it is becoming apparent that a subset of COVID-19 patients displays activated adaptive immune response, which augments hyper-inflammation, thereby leading to disease worsening.
T438 74658-74908 Sentence denotes In the subsequent section, we will specifically discuss the intricate role of T and B cells concerning their contribution to the development of the immunopathological state and how this critical antiviral immune response becomes awry during COVID-19.
T439 74910-74971 Sentence denotes Proinflammatory Cytokines Secreted by T Cells During COVID-19
T440 74972-75135 Sentence denotes Hyperinflammatory condition mediated by cytokines, chemokines and associated proinflammatory molecules which are secreted by both innate and adaptive immune cells.
T441 75136-75322 Sentence denotes However, during COVID-19, the relative contribution of adaptive immune cells towards proinflammatory molecules is still emerging, while the published studies suggest a complex interplay.
T442 75323-75528 Sentence denotes Profiling of 21 cytokines and chemokines in 39 patients and 24 healthy controls revealed increased levels of TH1 specific cytokines like IFN-γ, IL-2, and IL-12, and TH17 specific IL-17 in peripheral blood.
T443 75529-75659 Sentence denotes In comparison to the mild cases (n = 19), patients with severe disease (n = 10) condition had increased levels of these cytokines.
T444 75660-75779 Sentence denotes The limitation of this study was that the median age of severe cases was higher than in mild cases (Song et al., 2020).
T445 75780-75963 Sentence denotes Similarly, Zhou et al. (2020b) reported hyperactivated TH1 cell response with increased secretion of IFN-γ, GM-CSF, and IL-6 and with more robust expression in ICU cases than non-ICU.
T446 75964-76264 Sentence denotes Considering the age, gender and other associated factors, a large number of other studies have now confirmed that COVID-19 patients have increased levels of TH1 specific cytokines, with more robust levels seen in severe than mild cases (Huang C. et al., 2020; Xu Z. et al., 2020; Zhou et al., 2020b).
T447 76265-76406 Sentence denotes Similarly, CD8+ T cell-specific cytokines increased in COVID-19 patients, more pronounced in severe than mild condition (Zhou et al., 2020b).
T448 76407-76554 Sentence denotes Increased expression of GM-CSF was found in CD8+ T cells from ICU patients than non-ICU, while no difference was observed in IL-6 and TNF-α levels.
T449 76555-76852 Sentence denotes PBMCs derived from COVID-19 patients and stimulated in vitro showed an increase in expression of CCL2, CXCL10, Eotaxin, and IL-1RA, and stimulation of CD8+ T cells were associated with an increase in IFN-γ levels, which indicates the functional responsiveness of these cells (Mathew et al., 2020).
T450 76853-76954 Sentence denotes These studies thus suggest a robust activation of TH1 specific and CD8+ T cells in COVID-19 patients.
T451 76955-77067 Sentence denotes On the contrary, there are studies which show decreased cytokine expression by T cells in severe COVID-19 cases.
T452 77068-77198 Sentence denotes A study by Zheng H.Y. et al. (2020) showed a lower expression of IFN-γ, IL-2, and TNF-α in CD4+ T cells derived from severe cases.
T453 77199-77295 Sentence denotes Similarly, a decrease in IL-2+ CD8+ and IFN-γ+ CD8+ cells was also observed (Diao et al., 2020).
T454 77296-77587 Sentence denotes Although most studies point toward the robust activation and release of proinflammatory cytokines by CD4+ and CD8+ T cells, the discrepancy in latter studies could attribute to the functional exhaustion of these cells, which will we will discuss in section “Lymphocytopenia During COVID-19.”
T455 77588-77817 Sentence denotes Besides the presence of TH1 cytokines, TH2 cytokines like IL-4 and IL-5 and TH17 specific IL-17 were reported in some studies (Han et al., 2020; Huang C. et al., 2020; Song et al., 2020; Tan L. et al., 2020b; Xu Z. et al., 2020).
T456 77818-77992 Sentence denotes The presence of TH2 cytokines usually seen in mild cases may be accounted for by the presence of other respiratory conditions with TH2 specific response (Laing et al., 2020).
T457 77993-78323 Sentence denotes Overall, all these studies point toward the increased secretion of proinflammatory molecules by T lymphocytes in COVID-19, albeit with a heterogeneous response, which may be due to the variation in the age of the patients studied, different sampling times and presence of the comorbid condition, which needs further investigation.
T458 78325-78394 Sentence denotes Activation and Exhaustion Status of T Cells During COVID-19 Infection
T459 78395-78530 Sentence denotes The activation, exhaustion, and proliferation response of T and B cells are considered an integral determinant of the disease severity.
T460 78531-78802 Sentence denotes Unequivocally, studies have shown lymphocytopenia as a predictive marker which may also determine the disease severity in COVID-19 patients (Liu J. et al., 2020; Tan L. et al., 2020b; Wang et al., 2020b; Yang A.P. et al., 2020; Yang X. et al., 2020; Zhang et al., 2020a).
T461 78803-78918 Sentence denotes However, contradictory reports exist regarding the functional and exhaustion status of these cells during COVID-19.
T462 78919-79127 Sentence denotes Further, understanding these changes throughout the disease has remained a challenge, considering the complexity in the underlying immune response, comorbid condition, and previous exposure to the infections.
T463 79128-79287 Sentence denotes Peripheral blood study of a single patient (50-year male) revealed robust activation of CD4+ and CD8+ T cells marked by HLA-DR expression (Xu Z. et al., 2020).
T464 79288-79375 Sentence denotes However, the major limitation of this study was that only a single patient was studied.
T465 79376-79514 Sentence denotes Using multiparameter flow cytometry approach Kuri-Cervantes et al. (2020) studied 35 COVID-19 patients (n = 7 moderate and n = 28 severe).
T466 79515-79694 Sentence denotes The study revealed that a subset of severe cases displayed T cell activation as revealed by CD38 and HLA-DR expression in both CD4+ and CD8+ T cells (Kuri-Cervantes et al., 2020).
T467 79695-79889 Sentence denotes By analyzing, PBMCs derived from healthy (n = 5) and severe cases (n = 16), the authors found an increase in the percentage of cytotoxic CD8+ memory cells as revealed by perforin and granzyme B.
T468 79890-80005 Sentence denotes Similarly, a subset of severe cases had increased Ki-67 expressing CD4+ and CD8+ T cells, displaying proliferation.
T469 80006-80198 Sentence denotes At the same time, these findings revealed heterogeneous T cell response but overall suggested a skew towards the activation and proliferation status of these cells in a subset of severe cases.
T470 80199-80368 Sentence denotes The limitation of this finding is again the small sample size which may be the reason for the inconclusive findings of the T cell status concerning the disease severity.
T471 80369-80527 Sentence denotes Similar multiparameter flow cytometry approach was used by De Biasi et al. (2020) to study T cell response in healthy (n = 12) and COVID-19 patients (n = 21).
T472 80528-80638 Sentence denotes The study found activated status of CD4+ and CD8+ T cells as revealed by an increase in CD38+HLA-D population.
T473 80639-80781 Sentence denotes Activated status of the CD4+ T and CD8+ T cells was further confirmed by production of IFN-γ, TNF-α, IL-17, and IL-2 when stimulated in vitro.
T474 80782-80960 Sentence denotes The major limitation of this study was that the sample size was small, which restricted the comparison between the T cell responses across patients with various disease severity.
T475 80961-81103 Sentence denotes In another study, Song et al. (2020) showed the activated status of CD8+ T but not CD4+ T cells in severe (n = 9) than mild (n = 20) patients.
T476 81104-81260 Sentence denotes The activated status of CD8+ T cells reflected by the increased population of CD38+HLA-DR+, HLA-DR+, and CD38+HLA-DR+ marker expression (Song et al., 2020).
T477 81261-81426 Sentence denotes Further, CD8+ T cells were associated with increased cytolytic markers like granzyme B, perforin, and granulysin with more pronounced activation in severe than mild.
T478 81427-81554 Sentence denotes While across studies, it has become apparent that T cells show robust activation status in severe cases than mild and moderate.
T479 81555-81658 Sentence denotes These cells also exhibit exhaustion status, which may occur concomitantly with their activation status.
T480 81659-81882 Sentence denotes Deep immune profiling of 125 patients by Mathew et al. (2020) demonstrated that both CD4+ and CD8+ T cells exhibit activation status as revealed by coexpression of CD38 and HLA-DR which corresponded to the disease severity.
T481 81883-82008 Sentence denotes Further, these cells were also associated with concomitant expression of proliferation (Ki-67) and exhaustion (PD-1) markers.
T482 82009-82207 Sentence denotes This study thus suggests that hyperactivated status of T cells may eventually lead to their exhaustion, and thus these functional and exhaustion features of T cells may reflect the disease severity.
T483 82208-82362 Sentence denotes A study by Zheng M. et al. (2020) in a cohort of 68 COVID-19 patients revealed extensive CD8+ T cell exhaustion as shown by increased expression of NKG2A.
T484 82363-82590 Sentence denotes Intracellular cytokine staining (IFN-γ, IL-2, and granzyme B) further confirmed a decrease in the activation profile of these cells, which was more pronounced in severe (n = 55) than mild (n = 13) cases (Zheng M. et al., 2020).
T485 82591-82830 Sentence denotes As mentioned earlier in the study by Song et al. (2020) and De Biasi et al. (2020) T cells showed activation status that was also concomitantly seen with express of exhaustion markers PD-1 and TIM-3 on CD8+ T cells and TIM-3 on CD4+ cells.
T486 82831-82909 Sentence denotes The exhaustion was more pronounced in severe cases (n = 9) than mild (n = 20).
T487 82910-83015 Sentence denotes However, both these studies did not consider the age of the patients when comparing the disease severity.
T488 83016-83133 Sentence denotes Further, the study did not consider the temporal dynamics of these cells while measuring their functional properties.
T489 83134-83345 Sentence denotes In agreement, Zheng H.Y. et al. (2020) showed reduced functional activation of CD4+ T cells in severe (n = 6) than mild (n = 10) group as revealed by a lower proportion of IFN-γ and IL-2 expressing CD4+ T cells.
T490 83346-83445 Sentence denotes While IL-2 expressing CD4+ T cell population was also significantly lower in healthy vs mild group.
T491 83446-83626 Sentence denotes Further, CD8+ T cells displayed exhaustion as revealed by an increase in CTLA-4 in severe cases than mild and TGIT in severe than healthy, while PD-1 was more in mild than healthy.
T492 83627-83739 Sentence denotes Exhaustive states of both CD4+ and CD8+ T cells were also present in patients requiring ICU (Diao et al., 2020).
T493 83740-83871 Sentence denotes The exhaustive state was apparent by an increase in PD-1 and Tim-3 expression, which was more pronounced in CD8+ than CD4+ T cells.
T494 83872-84214 Sentence denotes These studies along with others thus suggest that robust activation followed by the exhaustion of CD4+ and CD8+ T cells may be responsible for the disease progression, while therapies like checkpoint inhibitors (anti-PD-1 antibody; NCT04268537) which may prevent T cell exhaustion and restore their functional state may benefit some patients.
T495 84215-84313 Sentence denotes More studies are necessary before using such an approach can be used for therapeutic intervention.
T496 84314-84433 Sentence denotes A post-mortem study of deceased COVID-19 patients conducted to find the status of these cells at the site of infection.
T497 84434-84603 Sentence denotes T cell profiling and their activation status in the lungs revealed an increase in the presence of CD4+ and CD8+ T cells exhibiting activation status (Song et al., 2020).
T498 84604-84717 Sentence denotes This increase in infiltration of these cells was concomitantly associated with their decline in peripheral blood.
T499 84718-84831 Sentence denotes Others presented a similar activation profile of CD8+ T cells (Kuri-Cervantes et al., 2020; Mathew et al., 2020).
T500 84832-85177 Sentence denotes This activated state of CD8+ T cells was consistently present across studies, with reports of immune profiling in BALF samples from COVID-19 patients, which showed increased CD4+ and CD8+ T cells in the lungs in both mild and severe cases along with the increased expression of CD8+ T cell cytolytic genes like GZMA and GZMK (Liao et al., 2020).
T501 85178-85376 Sentence denotes Thus, these studies point towards heterogeneous activation and exhaustion status of T cells in peripheral blood, while a more consistent activated status at the site of infection (lungs) (Figure 4).
T502 85377-85539 Sentence denotes FIGURE 4 T and B cell immune response during SARS-CoV-2 infection. (A) The activation status of CD4+ and CD8+ T in the circulation is indicated by CD38+ HLA-DR+.
T503 85540-85677 Sentence denotes These activated T cells are further recruited at the sites of infection (initially lungs) in the presence of their respective chemokines.
T504 85678-85895 Sentence denotes The activated CD4+ T cells are marked by the presence of cytokines like IFN-γ, IL-2, IL-12, IL-6, and GM-CSF, whereas activated CD8+T (cytotoxic T cells) are marked by the secretion of granzymes, perforins, and IFN-γ.
T505 85896-86224 Sentence denotes During SARS-CoV-2 infection, activated CD8+T cells exhibiting increased expression of granzyme A, B, and K (GZM-B, GZM-A, and GZM-K) were found in the lungs (Liao et al., 2020; Song et al., 2020; Zheng M. et al., 2020). (B) T cells were also found to exhibit exhausted state as marked by the expression of PD-1, Tim3, and NKG2A.
T506 86225-86491 Sentence denotes However, most studies showing exhausted T cells were confined to the peripheral blood, while lungs were mostly shown to have activated T cells but with concomitant expression of some exhaustive markers, suggesting that the activation state is followed by exhaustion.
T507 86492-86864 Sentence denotes The exhaustive T cells are marked by the reduced expression of respective chemokines and cytolytic granules. (C) Similarly, antibody-producing B cells (plasmablasts; PB) were shown to exhibit activation status as reflected by the expression of IL4R, TNFSF13B, and XBP1, while at the same time, the exhausted status of these cells was also reported in the peripheral blood.
T508 86865-86943 Sentence denotes Exhaustive state of B cells is reflected by a decrease in antibody production.
T509 86944-87133 Sentence denotes Further, it appears that unlike CD4+ T cells, the activation status of CD8+ T cells is more pronounced, which may account for their relatively faster exhaustion state (Wherry et al., 2007).
T510 87134-87342 Sentence denotes Interestingly, by studying the CD8+T cell response in convalescent patients, Habel et al. (2020) found that these cells skewed toward naïve, stem cell and central memory phenotypes, with low effector T cells.
T511 87343-87459 Sentence denotes While comparing the response with Influenza A viruses, SARS-CoV-2 directed CD8+ T exhibit relatively lower response.
T512 87460-87802 Sentence denotes Others have also shown a significant decline in CD8+ T cell subsets (naïve, effector, and memory) in COVID-19 patients, with a more pronounced decline in critical (n = 3) than severe (n = 5), and mild (n = 4), suggesting their robust activation during early disease followed by exhaustion during the critical condition (Wang W. et al., 2020).
T513 87803-87923 Sentence denotes On the contrary, CD4+ T cells were higher in the mild and critical cases than severe cases and healthy control (n = 12).
T514 87924-88153 Sentence denotes These results imply that the overall T cell response is heterogenous, while CD8+ response, though robust during infection and correlates with the disease severity; but the response may not be long-lasting, at least in some cases.
T515 88154-88235 Sentence denotes Both CD4+ and CD8+ T cells also exhibit dysregulated response (Qin et al., 2020).
T516 88236-88354 Sentence denotes Decreased levels of CD4+ regulatory cells as marked by CD3+ CD4+ CD25+ CD127low+ population was found in severe cases.
T517 88355-88452 Sentence denotes Similarly, the study found decreased CD8+ suppressor T cells (CD3+, CD8+, CD28+) in severe cases.
T518 88453-88681 Sentence denotes Overall, more comprehensive studies are warranted with larger cohort size, to profile local vs systemic T cell response and persistence simultaneously, and correlate these responses with disease severity in age-matched patients.
T519 88683-88723 Sentence denotes Impaired B Cell Response During COVID-19
T520 88724-88848 Sentence denotes Regulated and controlled B cell response is critical for the effective immune response against the CoVs, as discussed above.
T521 88849-88966 Sentence denotes However, under certain conditions, B cell response may be detrimental and aggravate the underlying disease condition.
T522 88967-89154 Sentence denotes A notion has emerged, which suggests that in COVID-19 patients, B cell number though reduced, but these cells display robust activation in some cases that correlate with disease severity.
T523 89155-89340 Sentence denotes Deep immune profiling integrated with computational approach revealed intricate relations of B cell response with clinical parameters at various stages of the COVID-19 disease severity.
T524 89341-89453 Sentence denotes These cells express proliferation (Ki67+), differentiation (CD27+ CD38+), as well as exhaustion markers (PD-1+).
T525 89454-89621 Sentence denotes More robust expression of these markers was observed in severe cases compared to mild-moderate, with an overall decrease in memory B cell number (Mathew et al., 2020).
T526 89622-89776 Sentence denotes Further, 70% of the patients reported have IgG and IgM S protein-specific antibodies, suggesting activation status of the antibody-secreting plasmablasts.
T527 89777-89948 Sentence denotes Thus, this study shows that B cells, in severe cases, display concomitant activation and exhaustion markers, while mild cases or healthy controls showed a normal response.
T528 89949-90045 Sentence denotes However, how this activated status of B cells had an impact on disease severity was not studied.
T529 90046-90266 Sentence denotes By looking at the alleged relationship of activated B cells with disease severity, Woodruff et al. (2020) showed robust activation status of extrafollicular B cells which resembled their behavior in autoimmune condition.
T530 90267-90508 Sentence denotes The activation status of these cells was found more pronounced in critically ill patients (n = 10) than non-critical (n = 7) and healthy control (n = 17), which correlated with SARS-CoV-2-specific antibody production and disease progression.
T531 90509-90727 Sentence denotes Further, an increase in antibody-secreting cells (ASCs) was found in critically ill cases compared to non-severe cases along with an increase in S protein-specific antibodies, probably with a non-neutralizing property.
T532 90728-90938 Sentence denotes This study shows that in some patients with a critical disease condition, robust B cell response and presence of SARS-CoV-2 antigen-specific antibodies may be associated with worsening of the disease condition.
T533 90939-91026 Sentence denotes The ASCs were identified as the population of cells with CD138+ and CD21low expression.
T534 91027-91115 Sentence denotes However, no comparison was drawn between various age groups concerning disease severity.
T535 91116-91252 Sentence denotes While across studies, B cell activation is apparent in severe cases, it is subsequently associated with a sharp decline in their number.
T536 91253-91393 Sentence denotes Various mechanisms may be responsible for this decline, among which B cell exhaustion is one, but still poorly understood (Yi et al., 2010).
T537 91394-91501 Sentence denotes A recent study has provided mechanistic insights into how some cases of COVID-19 exhibit low B cell number.
T538 91502-91730 Sentence denotes Kaneko et al. (2020) studied the post-mortem samples (n = 11) of thoracic lymph nodes and spleens and found that Bcl-6+ germinal center (GC) B cells highly reduced in these patients in comparison to non-COVID-19 control (n = 6).
T539 91731-91879 Sentence denotes This decline in GC was also associated with a decrease in TFH cell differentiation and an increase in the number of TH1 cells (Kaneko et al., 2020).
T540 91880-91958 Sentence denotes Further, an increase in expression of TNF-α levels was found in the follicles.
T541 91959-92191 Sentence denotes Based on previous studies that TNF-α inhibits the lymphoid follicular development, and high levels of this pleiotropic cytokine is the hallmark of COVID-19, the authors attributed the reduction in GC to high levels of this cytokine.
T542 92192-92365 Sentence denotes In addition to the study in post-mortem samples, the authors conducted B cell analysis in peripheral blood samples from COVID-19 patients at different stages of the disease.
T543 92366-92662 Sentence denotes In line with the post-mortem data, patients with severe disease condition (n = 25) had a significant decrease in the number of naïve B cells, CD19+ B cells, and follicular B cell subsets in comparison to the healthy controls (n = 4), convalescent patients (n = 39), and moderate patients (n = 4).
T544 92663-92757 Sentence denotes Thus, this study provides a probable cause for the B cell decline in severe cases of Covid-19.
T545 92758-92929 Sentence denotes However, there was a significant difference in the mean age of severe patients (higher between 58 and 60) than the control, convalescent, and moderate group (30–45 years).
T546 92930-93015 Sentence denotes Thus, the effect of age on the decline in B cells cannot be undermined in this study.
T547 93016-93215 Sentence denotes More studies are needed to specifically look into the B cell number and activation status in COVID-19 patients concerning the disease severity to get a clear understanding of the role of these cells.
T548 93217-93246 Sentence denotes Antibody Dynamics in COVID-19
T549 93247-93385 Sentence denotes Antibody-based therapy is being considered as a potential intervention for COVID-19, owing to the successful preliminary results with CPT.
T550 93386-93564 Sentence denotes However, this treatment approach may be associated with the risk of exacerbating COVID-19 severity, based on the experience from previous viral infections (Salazar et al., 2017).
T551 93565-93783 Sentence denotes Further, like previous SARS-CoV infections, antibody response may not always favor viral clearance, instead of contributing to the underlying immunopathology in some instances (Zhang et al., 2006; Newton et al., 2016).
T552 93784-94013 Sentence denotes This immunopathological state may thus attribute to factors such as robust and unregulated activation of B cells, ADE, presence of cross-reactive but non-neutralizing antibodies, and failure to mount a controlled B cell response.
T553 94014-94210 Sentence denotes Across studies, higher antibody titers detected in patients with severe and critical condition in comparison to non-severe cases (Long et al., 2020a; Gudbjartsson et al., 2020; Zhao et al., 2020).
T554 94211-94476 Sentence denotes One can argue that higher antibody titer should be beneficial to provide an adequate antiviral response but can be countered by the finding that higher antibody titers found in a large number of severe cases and patients requiring ventilation (Kaneko et al., 2020).
T555 94477-94640 Sentence denotes This contradiction is yet to resolve, and the emerging data suggest that higher antibody response may reflect the over-activation and uncontrolled B cell response.
T556 94641-94765 Sentence denotes Zheng M. et al. (2020) showed the presence of RBD-specific IgG and IgA antibodies in patients with severe disease condition.
T557 94766-94841 Sentence denotes The study included 13 severe and 41 non-severe cases of various age groups.
T558 94842-95001 Sentence denotes Along with increased IgG and IgA levels, severe cases also had an increased number of antibody-secreting cells and TFH cells, which aid in antibody production.
T559 95002-95170 Sentence denotes Further, a close correlation of proinflammatory cytokines and chemokines like IL-6, CXCL10 and complement activation marker C5a found with the severe disease condition.
T560 95171-95298 Sentence denotes This study provided a direct relation of inflammatory response with humoral immune response in context to the disease severity.
T561 95299-95401 Sentence denotes However, the antigen-neutralizing property of these SARS-CoV-2 specific antibodies was not determined.
T562 95402-95585 Sentence denotes Further, a low sample size of severe cases was another limiting factor to provide a definitive conclusion that robust antibody response may positively correlate with disease severity.
T563 95586-95718 Sentence denotes Similarly, Zhao et al. (2020) studied antibody response in 173 clinically diagnosed COVID-19 patients with a median age of 48 years.
T564 95719-95871 Sentence denotes Among these, nine patients (three critical and six non-critical) studied longitudinally for the relation of antibody response with the disease severity.
T565 95872-95951 Sentence denotes Antibody titer was higher in the critical patients as compared to non-critical.
T566 95952-96165 Sentence denotes This higher titer of antibodies was not reflected by the clearance of the virus, thus suggesting that antibody response in critical cases may be associated with worse disease outcome rather than protective effect.
T567 96166-96263 Sentence denotes However, like other studies, this study also suffers from the same limitation of low sample size.
T568 96264-96478 Sentence denotes In line with the notion that antibody response is higher in severe patients, a large population study (n = 30,576 persons from Iceland) (Gudbjartsson et al., 2020) conducted in Iceland revealed similar observation.
T569 96479-96667 Sentence denotes The study provided a comprehensive account of the relation of antibody response concerning age, sex, body-mass index, drugs habits like smoking and the use of anti-inflammatory medication.
T570 96668-96836 Sentence denotes Results show that patients with smoking habit and who were on anti-inflammatory medication, had lower antibody levels, while body mass index had a positive association.
T571 96837-97026 Sentence denotes The data thus suggest that antibody response may not always favor clearance of the virus, but in some instances, higher antibody levels may make the patients more vulnerable to the disease.
T572 97027-97175 Sentence denotes This detrimental relation of antibody response with poor disease outcome was also prevalent in the previous SARS-CoV infection (Zhang et al., 2006).
T573 97176-97421 Sentence denotes In a study on the sera samples obtained from SARS-CoV infected patients, a faster S protein-specific antibody response was found in patients who did not survive (14.7 days), as compared with the patients who recovered from the disease (20 days).
T574 97422-97554 Sentence denotes Further, the antibody titer was significantly higher in the deceased patients with faster production than in the recovered patients.
T575 97555-97746 Sentence denotes To mechanistically understand why antibody response has a more detrimental effect than protective, Liu et al. (2019) studied viral antibody response in animal models (Chinese rhesus monkeys).
T576 97747-97916 Sentence denotes When animals infected with the SARS-CoV and adoptively transferred with anti-S protein IgG could not prevent the infection but instead displayed severe disease symptoms.
T577 97917-98114 Sentence denotes Presence of the S protein antibody abrogated wound healing, induced macrophage/monocyte infiltration into the lungs and caused the release of proinflammatory cytokine followed by acute lung injury.
T578 98115-98281 Sentence denotes This study thus demonstrated that the presence of S protein-specific antibody might have a deleterious effect in inducing lung injury, irrespective of the viral load.
T579 98282-98413 Sentence denotes However, since mechanistic details are difficult to discern in clinical samples, more studies in animal models need to be explored.
T580 98414-98703 Sentence denotes Further, owing to the dynamics of antibody response in clinical samples concerning underlying disease condition, age, and genetic factors; animal models will provide a cleaner system to delineate the antibody dynamics with respect to disease severity (Guan et al., 2020; Hou et al., 2020).
T581 98704-98833 Sentence denotes Contrary to B cell activation, some studies have shown lower antibody durability in both mild and severe cases (Yu et al., 2020).
T582 98834-98988 Sentence denotes In a longitudinal study on a 26-year-old woman with a moderate disease condition, antibody response disappeared within three months (Liu A. et al., 2020).
T583 98989-99190 Sentence denotes In a sizable cohort of samples, asymptomatic patients (n = 37 with median age 41 years) had relatively lower durability of the IgG and IgM antibodies in comparison to the symptomatic patients (n = 37).
T584 99191-99304 Sentence denotes Further, the viral shedding in the asymptomatic group was higher than the symptomatic group (Long et al., 2020b).
T585 99305-99507 Sentence denotes Similarly, Ibarrondo et al. has shown the same antibody durability in 34 COVID-19 patients with a mean age of 43 years when studied longitudinally for a period of upto 4 months (Ibarrondo et al., 2020).
T586 99508-99629 Sentence denotes The authors found a significant decline in IgG antibodies in the sera of convalescent patients with mostly mild symptoms.
T587 99630-99795 Sentence denotes A declining trend was seen for multiple SARS-CoV-2 antibodies like IgG N, IgM, IgG S1, and IgA S1 in the longitudinal analysis (n = 487) (Gudbjartsson et al., 2020).
T588 99796-99947 Sentence denotes In another longitudinal study, the disappearance of S and N protein-specific antibodies was observed within 3 months of recovery (Liu A. et al., 2020).
T589 99948-100276 Sentence denotes Based on these reports, we can infer that the antibody response in some COVID-19 patients may not be long-lasting, which poses a challenge for antibody-based therapy and vaccine research—further, these data caution towards chances of reinfection, as shown to be the case with other seasonal coronaviruses (Edridge et al., 2020).
T590 100277-100415 Sentence denotes However, larger cohort size and longer time frame longitudinal studies are needed to find the durability of antibody response in COVID-19.
T591 100416-100567 Sentence denotes Further, a comparison of various disease states with corresponding antibody response will provide clearer insight as to how this response is regulated.
T592 100568-100802 Sentence denotes It appears that in patients with severe disease symptoms, TNF-α may influence the GC and hence B cell number (Kaneko et al., 2020), whether the same holds for asymptomatic patients with compromised antibody durability remains elusive.
T593 100803-100936 Sentence denotes This dynamic antibody response is critical while considering convalescent plasma therapy (CPT) for severe or critically ill patients.
T594 100937-101069 Sentence denotes If a patient already has sufficient antibodies, CPT may not be a viable treatment option (Anderson et al., 2020; Duan et al., 2020).
T595 101070-101213 Sentence denotes While many studies have reported success with CPT, some studies have shown no added beneficial effects with this approach (Li L. et al., 2020).
T596 101214-101529 Sentence denotes Thus, pre-caution should be taken while using this approach, i.e., if a patient already has adequate virus-specific antibodies or presence of cross-reactive and auto-antibodies, plasma therapy may do more harm than good, which may be the reason with non-responsiveness of CPT in some patients (Nagoba et al., 2020).
T597 101531-101595 Sentence denotes SARS-CoV-2 Antibody Cross-Reactivity and Neutralization Property
T598 101596-101680 Sentence denotes A range of SARS-CoV specific antibodies have shown cross-reactivity with SARS-CoV-2.
T599 101681-101765 Sentence denotes These antibodies target S protein and mostly the RBD region (Hoffmann et al., 2020).
T600 101766-101914 Sentence denotes Monoclonal antibodies against SARS-CoV such as CR3022 and S309 have shown cross-reactivity with SARS-CoV-2 (Pinto et al., 2020; Wang et al., 2020a).
T601 101915-102171 Sentence denotes Similarly, in a study of 285 patients, S protein-specific antibodies from SARS-CoV showed cross-reactivity with CoV-2 N protein in a subset of patients (n = 5), whereas no-cross reactivity was detected against S1 subunit of SARS-CoV-2 (Long et al., 2020a).
T602 102172-102289 Sentence denotes Thus, the cross-reactive nature of some of these antibodies may ensure their efficacy against multiple coronaviruses.
T603 102290-102432 Sentence denotes However, at the same time, these cross-reactive antibodies should also have neutralizing property; otherwise, they will have a harmful effect.
T604 102433-102557 Sentence denotes A recent study explored the cross-reactive and neutralization property of these antibodies simultaneously (Lv et al., 2020).
T605 102558-102764 Sentence denotes This study used plasma from 15 SARS-CoV-2 and 7 SARS-CoV patients and found a high degree of cross-reactivity between the antibody response from these samples, but a very low antibody neutralizing property.
T606 102765-102846 Sentence denotes These results were further confirmed in animal models of SARS-CoV-2 and SARS-CoV.
T607 102847-103025 Sentence denotes While S309 antibody showed better neutralization property against SARS-CoV-2, the neutralization properties for CR3022 are not yet known (Pinto et al., 2020; Wang et al., 2020a).
T608 103026-103224 Sentence denotes Thus, although a high degree of cross-reactivity of the antibody response from SARS-CoV-2 can be found with other related CoVs, the neutralizing property of these antibodies may be epitope specific.
T609 103225-103451 Sentence denotes The weak neutralizing property of such cross-reactive antibodies should thoroughly be tested before usage as a therapeutic intervention, to prevent the complications which may arise due to antibody-dependent enhancement (ADE).
T610 103452-103534 Sentence denotes These factors also become essential while considering convalescent plasma therapy.
T611 103535-103652 Sentence denotes In an elegant recent study, Cao et al. (2020) performed sc-RNA-seq of B cells from 60 convalescent COVID-19 patients.
T612 103653-103777 Sentence denotes The study led to the identification of 14 neutralizing antibodies, among which one (BD-368-2) showed the most potent effect.
T613 103778-103908 Sentence denotes BD-368-2 was further explored for its efficacy in animal models and showed therapeutic potential in SARS-CoV-2 transgenic animals.
T614 103909-104149 Sentence denotes Further, the study suggested the use of two different monoclonal antibodies targeting different epitopes as a more viable therapeutic intervention than a single antibody, which is impressive considering the emerging mutations in SARS-CoV-2.
T615 104150-104306 Sentence denotes Thus, more research in this direction is needed to find antibodies with potent neutralization property for targeted therapy to alleviate the disease burden.
T616 104308-104350 Sentence denotes Antibody Dependent Enhancement in COVID-19
T617 104351-104461 Sentence denotes Non-neutralizing but cross-reactive antibodies may lead to ADE and hence enhance the immunopathological state.
T618 104462-104707 Sentence denotes ADE can occur through various pathways, the most important among which include endocytosis of antibody conjugated virus by the phagocytic cells (via Fc gamma receptor IIa (FcγRIIa) and enhanced antibody immune complex formation (Kulkarni, 2020).
T619 104708-104913 Sentence denotes Virus uptake by the phagocytic cells induces robust propagation and hence may further aggravate the disease condition, while antibody immune complex formation may generate a high pro-inflammatory response.
T620 104914-105111 Sentence denotes Experience from previous viral infections has shown that ADE may lead to worse disease outcome in some patients with the presence of non-neutralizing antibodies, reviewed by Lee W.S. et al. (2020).
T621 105112-105207 Sentence denotes In vitro studies on monocytes and macrophages have shown ADE in SARS-CoV (Flipse et al., 2016).
T622 105208-105335 Sentence denotes However, no definitive clinical data is available that indicates the occurrence of ADE during SARS-CoV or SARS-CoV-2 infection.
T623 105336-105558 Sentence denotes Nevertheless, based on the substantial cross-reactivity between various epitope regions of CoVs, some patients may exhibit ADE due to the presence of cross-reactive but non-neutralizing antibodies from previous infections.
T624 105560-105594 Sentence denotes Unconventional T Cells in COVID-19
T625 105595-105749 Sentence denotes Bronchial alveolar lavage fluid analysis of 3 COVID-19 patients reveals a high number of NKT cells during the acute phase of infection (Kim et al., 2020).
T626 105750-105825 Sentence denotes This increase in NKT cells was similarly reflected in the peripheral blood.
T627 105826-105913 Sentence denotes Conversely, a decline in the number of these cells was found during the recovery phase.
T628 105914-106111 Sentence denotes These results thus suggest a close correlation of the NKT cell activity in COVID-19 and the presence of these cells may be required for the clearance of virus during the initial phase of infection.
T629 106112-106274 Sentence denotes Concomitantly, increased infiltration and activity of these cells may lead to a more severe outcome associated with eosinophilic pneumonia, as shown in one study.
T630 106275-106403 Sentence denotes However, no direct correlation of these cells types with disease severity was found, probably due to meagre sample size (n = 3).
T631 106404-106574 Sentence denotes Further, the samples used in this study were collected at different time points after the onset of symptoms, which may have complicated the interpretation of the results.
T632 106575-106878 Sentence denotes In another study on 30 COVID-19 patients with a varied range of disease severity from mild, moderate to severe, a reduction in the total peripheral blood NKT cells was seen across groups, with no difference in the overall number between ICU (n = 10) and non-ICU patients (n = 11) (Mazzoni et al., 2020).
T633 106879-107085 Sentence denotes Similarly, a study by Jouan et al. (2020) found a decrease in NKT and MAIT cells in the peripheral blood of COVID-19 patients (n = 30, with varied disease severity) as compared to healthy controls (n = 20).
T634 107086-107361 Sentence denotes This decline in circulating MAIT cells was concomitantly associated with an increase in these cells in the endotracheal aspirates (ETA) obtained from critically ill patients who needed mechanical ventilation (n = 12), while no changes in NKT cell number in ETA were detected.
T635 107362-107521 Sentence denotes The presence of circulating IL-18 reflected the activation of these cells, and the expression of PD-1 suggested subsequent exhaustion throughout the infection.
T636 107522-107679 Sentence denotes This study thus indicates that the presence of the activated status of these unconventional T cells may serve as a predictive assessment of disease severity.
T637 107680-107915 Sentence denotes More research about the activation, proliferation and differentiation status of these cells to the disease severity and local vs systemic effect is needed to fully understand their contribution in COVID-19 (Chen and John Wherry, 2020).
T638 107917-107948 Sentence denotes Lymphocytopenia During COVID-19
T639 107949-108225 Sentence denotes A drastic decrease in the number of circulating lymphocytes (lymphocytopenia) in severe and critically ill COVID-19 patients is now well appreciated (Huang C. et al., 2020; Liao et al., 2020; Liu et al., 2020a; Mathew et al., 2020; Zhou F. et al., 2020; Zhou P. et al., 2020).
T640 108226-108352 Sentence denotes Interestingly, restoration in the lymphocyte count is also consistently seen during the recovery phase (Chen Y. et al., 2020).
T641 108353-108489 Sentence denotes Based on these early findings, lymphocytopenia is considered a predictive indicator of COVID-19 disease severity (Tan L. et al., 2020b).
T642 108490-108708 Sentence denotes Although the molecular mechanisms associated with lymphocytopenia during SARS-CoV-2 are not known, emerging evidence suggests the role of multiple factors based on the correlations drawn from previous viral infections.
T643 108709-109037 Sentence denotes The decline in lymphocyte numbers in circulation can be attributed to altered chemokine and cytokine signaling responsible for the recruitment and activation/inhibition of these cells, increased infiltration to the site of infection, and cell death by apoptosis and/or necrosis (Wherry and Kurachi, 2015; Walling and Kim, 2018).
T644 109038-109224 Sentence denotes Immune profiles of COVID-19 patients show adequate levels of chemokines and cytokines involved in the maintenance of T and B cell phenotypes (Yang X. et al., 2020; Yang Y. et al., 2020).
T645 109225-109337 Sentence denotes Chemokines and cytokines responsible for CD8+ T cells priming and chemotaxis were also detected in the patients.
T646 109338-109568 Sentence denotes Similarly, cytokines responsible for B cell activation and proliferation signals were sufficiently present, thus excluding the possibility that lymphocytopenia may be a result of impaired activation signals or chemokine signaling.
T647 109569-109796 Sentence denotes Interestingly, a recent study suggests that severely ill COVID-19 patients had lower levels of activated (CD11a+) and terminally differentiated (CD57+) peripheral blood CD4+ and CD8+ T cells (which are also S-protein reactive).
T648 109797-109935 Sentence denotes The decline in the number of these cells can attribute to their concomitant migration to the infected regions under inflammatory response.
T649 109936-110130 Sentence denotes Similarly, another study has shown lymphocytopenia in peripheral blood along with a concomitant increase in the activation profile and the number of these cells in the lungs (Song et al., 2020).
T650 110131-110287 Sentence denotes Homing of these activated T cells to the site of infection may thus be associated with the worsening of the disease by amplifying the proinflammatory state.
T651 110288-110390 Sentence denotes A single patient analysis revealed increased CD4+ and CD8+ T cells in the BALF (Voiriot et al., 2020).
T652 110391-110602 Sentence denotes ScRNA-seq in BALF followed by cluster analysis revealed the presence of CD8+ T cells with proliferative phenotype in severe cases, whereas moderate cases exhibited clonal expansion phenotype (Liao et al., 2020).
T653 110603-110879 Sentence denotes From these accounts, it is indicative that increased migration of activated T cells to the site of infection may be one of the reasons for lymphocytopenia (in the blood) and the remaining T cells in the blood may eventually become dysfunctional (exhausted) as discussed below.
T654 110880-111034 Sentence denotes The decline in circulating lymphocyte number in COVID-19 patients can also attribute to the ‘exhausted’ state of these cells (Chen and John Wherry, 2020).
T655 111035-111204 Sentence denotes The heightened viral load and presence of specific inhibitory signals bring about changes in the transcriptional and effector profile of T cells in a coordinated manner.
T656 111205-111400 Sentence denotes Initially, they lose their property to secrete effector cytokines and gradually proceed to reduced expression of essential maintenance and activation surface receptors (Wherry and Kurachi, 2015).
T657 111401-111591 Sentence denotes A subsequent increase in the expression of inhibitory receptors and associated morphological changes result in the elimination of these cells from the circulation (Wherry and Kurachi, 2015).
T658 111592-111867 Sentence denotes CD4+ T cell exhaustion determines their insufficient secretion of effector molecules like IL-2, IL-10, IL-21, IFN-γ and TNF-α with a concomitant increase in inhibitory molecular signaling by PD-1, CTLA-4, LAG-3, CD244 (2B4), and TIM-3 (Blank et al., 2019; Dong et al., 2019).
T659 111868-111984 Sentence denotes Similarly, CD8+ T cell exhaustion is determined by reduced expression of IL-2, IFN-γ, TNF-α, and cytolytic granules.
T660 111985-112246 Sentence denotes Besides, decreased expression of T cell maintenance receptors CD122 and CD127, and increase in inhibitory receptor signaling via PD-1, CTLA-4, NKG2A, TIGIT, LAG-3, CD244 (2B4), and CD160 also mark their exhaustion (Wherry and Kurachi, 2015; Blank et al., 2019).
T661 112247-112471 Sentence denotes B cell exhaustion is also demonstrated similar to T cell exhaustion with an expression of inhibitory receptors PD-1, CD22, and LAIR-1 but the exhaustion profile of these cells is relatively unexplored (Moir and Fauci, 2014).
T662 112472-112600 Sentence denotes A large body of evidence suggests functional exhaustion of CD8+ T and CD4+ T cells in the peripheral blood of COVID-19 patients.
T663 112601-112798 Sentence denotes In some instances, exhaustion markers are concomitantly expressed along with activation and proliferation markers, as discussed above (Diao et al., 2020; Mathew et al., 2020; Mazzoni et al., 2020).
T664 112799-112946 Sentence denotes Moreover, increased expression of exhaustion-related genes like BATF, IRF4, and CD274 also correlated with disease severity (Hadjadj et al., 2020).
T665 112947-113064 Sentence denotes Interestingly, increased apoptosis of T cells became evident in severe cases as compared to mild/moderate conditions.
T666 113065-113209 Sentence denotes Thus, one way to explain lymphocytopenia in COVID-19 patients is that after the onset of symptoms, T cells are primed to overcome the infection.
T667 113210-113418 Sentence denotes However, in cases where viral infection persists, these cells attain robust activation, which may do more harm than good, as seen in severe and critically ill patients reviewed by Chen and John Wherry (2020).
T668 113419-113633 Sentence denotes Thus, the exhaustion of these cells precedes robust activation response, and eventually, they get eliminated from the circulation, as has been seen with previous viral infections (Wherry, 2011; Blank et al., 2019).
T669 113634-113812 Sentence denotes For example, during acute infection by lymphocytic choriomeningitis virus (LCMV), CD8+ T cells were shown to exhibit functional activation status and develop into memory T cells.
T670 113813-113995 Sentence denotes In contrast, during chronic infection, CD8+ T cells had impaired effector function and displayed profound exhaustion followed by apoptosis (Barber et al., 2006; Wherry et al., 2007).
T671 113996-114210 Sentence denotes Similarly, CD8+ T cell exhaustion is well known during persistent human immunodeficiency virus (HIV) infection, marked by robust expression of exhaustion markers like PD-1 (Day et al., 2006; Petrovas et al., 2006).
T672 114211-114384 Sentence denotes Following exhaustion, these cells are eliminated from the circulation, which is responsible for the decline in their number with long-term infection (Petrovas et al., 2009).
T673 114385-114674 Sentence denotes In addition to transcriptional changes that lead to exhaustion during chronic viral infection, the presence of secretory inhibitory molecules has been implicated in lymphocyte exhaustion with a prominent role of IL-10 and TGF-β in CD8+ T cell exhaustion (Wherry, 2011; Blank et al., 2019).
T674 114675-114830 Sentence denotes Increased levels of these cytokines in COVID-19 patients may also suggest their potential role in CD8+ T cell exhaustion (Chen, 2020; Liu A. et al., 2020).
T675 114831-114992 Sentence denotes Furthermore, severe COVID-19 patients had elevated lactic acid levels which is a known inhibitor of T cell function (Fischer et al., 2007; Tan L. et al., 2020b).
T676 114993-115085 Sentence denotes Another vital aspect of lymphocytopenia is direct cell death by the virus during infections.
T677 115086-115228 Sentence denotes HIV is a well-known example wherein CD4+ T cells undergo activation-induced cell death by the virus (Day et al., 2006; Petrovas et al., 2009).
T678 115229-115360 Sentence denotes Though respiratory viruses are not known to induce T cell apoptosis directly, virus-activated secondary factors may be responsible.
T679 115361-115516 Sentence denotes For example, T cell apoptosis was seen by the enhanced expression of death receptors during the infection of influenza virus (H5N1) (Boonnak et al., 2014).
T680 115517-115723 Sentence denotes MERS infection was also associated with T cell apoptosis by the virus-mediated activation of intrinsic and extrinsic pathways of cell death, resulting in their depletion from circulation (Chu et al., 2014).
T681 115724-115826 Sentence denotes The MERS infection was abortive in these cells, suggesting indirect activation of cell death pathways.
T682 115827-115990 Sentence denotes A few in vitro studies have shown low replication of SARS-CoV in T cells and the absence of any significant cell death (Chan and Chen, 2008; Wang X. et al., 2020).
T683 115991-116188 Sentence denotes Whether SARS-CoV-2 infects, T cells are currently unknown, but it appears that T cell decline during COVID-19 cannot be attributed to direct cell death by the virus but to the exhaustion mechanism.
T684 116189-116545 Sentence denotes In addition to the mechanism mentioned above associated with lymphocytopenia, secondary signaling mediated via engagement of death receptors, increased ROS, HMGB1 and other death-inducing agents released by the infected and damaged ATII cells may also be implicated in T cell decline (Kaminskyy and Zhivotovsky, 2010; Juno et al., 2017; Zhan et al., 2017).
T685 116546-116757 Sentence denotes Thus, based on these early findings, lymphocyte exhaustion may be driven by multiple factors that actively engage in rendering these cells ineffective, followed by their subsequent elimination (lymphocytopenia).
T686 116758-116890 Sentence denotes Overall, a clear picture is emerging, which strongly indicates lymphocytopenia as a predictive marker for COVID-19 disease severity.
T687 116891-117110 Sentence denotes Along with increased neutrophil number, the blood lymphocyte count serves as a better prognostic marker and reflects the immunopathological state of the patients (Giamarellos-Bourboulis et al., 2020; Liu et al., 2020b).
T688 117111-117240 Sentence denotes Further, based on these emerging studies, it is becoming evident that T cell response is heterogeneous during COVID-19 infection.
T689 117241-117461 Sentence denotes While peripheral blood may exhibit lymphocytopenia, and mostly exhausted status of these cells, the site of infection is associated with an activated profile of the cells and hence determines the severity of the disease.
T690 117462-117551 Sentence denotes Thus, caution should be exercised while designing therapeutic interventions for COVID-19.
T691 117552-117643 Sentence denotes The underlying immunological state should be borne in mind while considering the treatment.
T692 117644-117861 Sentence denotes Patients with lymphocytopenia and elevated functional and activation status of T cells may benefit from immunomodulatory approaches like mesenchymal stem cells, which are currently under clinical trials (NCT04377334).
T693 117862-118081 Sentence denotes Patients with imperfect T cell and B cell responses may benefit from convalescent plasma therapy, whereas patients with impaired interferon response may respond better to interferon therapies (NCT04350671; NCT04388709).
T694 118082-118248 Sentence denotes Thus, before a vaccine is available, a rational way to recommend therapy for severe cases of COVID-19 should be based on the patient’s underlying immunological state.
T695 118249-118360 Sentence denotes However, the treatment options become challenging when the patients exhibit cytokine storm and associated ARDS.
T696 118361-118564 Sentence denotes Moreover, it is imperative to analyze the T and B cell response by considering the age of the patient, comorbid condition, severity score, time of sample collection, and the method used for the analysis.
T697 118565-118775 Sentence denotes Because, the adaptive immune response is highly sensitive to these factors, and undermining them may thus further complicate our understanding of the development of the immunopathological state during COVID-19.
T698 118777-118812 Sentence denotes Cytokine Storm in COVID-19 Patients
T699 118813-119019 Sentence denotes Severe and critically ill COVID-19 patients exhibit cytokine storm (CS) as a reflection of the hyperimmune activation mediated by lung resident and infiltrated inflammatory immune cells, as mentioned above.
T700 119020-119224 Sentence denotes CS is manifested by the release of potent inflammatory cytokines, chemokines, and in some instances, interferons (as a late response) into the circulation that serves as an indicator of early lung damage.
T701 119225-119381 Sentence denotes Though the term CS is generally used with cytokine release syndrome (CRS) during CAR-T cell immunotherapy, it can reflect different pathological conditions.
T702 119382-119516 Sentence denotes While IL-6, TNF-α, and IL1-β predominantly represent CRS, CS is a much more complex response mounted by a range of inflammatory cells.
T703 119517-119683 Sentence denotes Further, differences are also apparent in the kinetics, and the concentration of the cytokines released, as discussed in a recent review (Vardhana and Wolchok, 2020).
T704 119684-119933 Sentence denotes Data from moderate, severe, critically ill, and recovered patients reveal a close correlation between the presence of proinflammatory cytokines with disease severity (Huang C. et al., 2020; Liao et al., 2020; Liu J. et al., 2020; Zhao et al., 2020).
T705 119934-119987 Sentence denotes Clinical evaluation of 41 COVID-19 patients (Non-ICU:
T706 119988-119999 Sentence denotes 28 and ICU:
T707 120000-120201 Sentence denotes 13) for over 26 chemokines and cytokines revealed increased levels of 16 of them such as IL-1β, IL-1RA, IL-17, IL-8, IL-9, IL-10, basic FGF, G-CSF, GM-CSF, IFN-γ, CXCL10, CCL2, CCL3, CCL4, PDGF, TNF-α.
T708 120202-120409 Sentence denotes In comparison to non-ICU cases, patients admitted to ICU exhibited increased levels of IL1-β, IFN-γ, and IL-6, suggesting TH1 immune cell response as reported previously for SARS-CoV (Huang C. et al., 2020).
T709 120410-120604 Sentence denotes Further, higher levels of G-CSF, CXCL10, CCL2, CCL3, and TNF-α indicated activation of monocytes and macrophages and damage to lung epithelial cells that were strongly correlated with ICU cases.
T710 120605-120786 Sentence denotes The strength of this study is that this is the first comprehensive cytokine profiling study of the COVID-19 patients, where disease severity was compared with the cytokine response.
T711 120787-121039 Sentence denotes The major limitation with this study is the small sample size for comparison between groups, and the use of lower respiratory specimen for testing rather nasopharyngeal swab sample – which is a sensitive specimen and commonly used for COVID-19 testing.
T712 121040-121209 Sentence denotes Working on relatively similar sample size (n = 40), Liu J. et al. (2020) found increased serum levels of IL-2, IL-6, IL-10 and IFN-γ corresponding with disease severity.
T713 121210-121319 Sentence denotes By performing longitudinal analysis, IL-6, IL-10 levels were consistently increased in severe cases (n = 13).
T714 121320-121588 Sentence denotes Besides small sample size, the major limitation with this study was that most of the patients had a comorbid condition like diabetes, hypertension, fungal infection and other chronic ailments, which may complicate the data interpretation and comparison between groups.
T715 121589-121827 Sentence denotes By working on a relatively larger cohort (n = 799), Chen T. et al. (2020) found that increased levels of IL-2R, IL-6, IL-8, IL-10, TNF-α in patients who had to succumb to the disease (n = 113) as compared to those who recovered (n = 161).
T716 121828-121869 Sentence denotes However, unlike the study by Huang et al.
T717 121870-121941 Sentence denotes IL-1β was not found to be significantly increased in deceased patients.
T718 121942-122124 Sentence denotes This discrepancy could be because the samples used by Huang C. et al. (2020) were from critically ill (5 deceased out of 13) patients, whereas Chen et al. analyzed deceased patients.
T719 122125-122242 Sentence denotes Thus, observed differences in levels of cytokines may reflect the disease severity and underlying comorbid condition.
T720 122243-122451 Sentence denotes In addition to the peripheral blood profiles, transcription profiling of BALF revealed higher expression of IL-10, CCL2, CXCL10, CCL3, and CCL4, a representation of lung immunopathology. (Xiong et al., 2020).
T721 122452-122769 Sentence denotes Similarly, in another study measurement of IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17, IFN-α, IFN-γ, and TNF-α were performed in the BALF, and the results revealed a significant increase in IL-1β, IL-6, and IL-8 levels in critically ill patients as compared to moderate condition (Liao et al., 2020).
T722 122770-123033 Sentence denotes BALF fluid analysis of 8 COVID-19 patients by Zhou Z. et al. (2020) also showed upregulation of key chemokine transcripts that are involved in the recruitment of inflammatory cells (IL1RN, IL1β, CXCL17, CXCL8, CXCL1, CXCL2, CCL2, and CCL7) (Zhou Z. et al., 2020).
T723 123034-123185 Sentence denotes ScRNA-seq analysis of BALF also revealed increased expression of CXCL9, CXCL10, CXCL11, and CXCL16 in all tested COVID-19 patients (Liao et al., 2020).
T724 123186-123327 Sentence denotes Lung macrophages displayed increased transcripts of IL-1β, IL-6, TNF-α along with chemokines like CCL2, CCL3, CCL4, and CCL7 in severe cases.
T725 123328-123551 Sentence denotes In terms of the contribution by the lung resident cells, tissue immunohistochemistry data revealed increased levels of IL-6, TNF-a and IL-10 in the AMs of biopsy samples obtained from deceased patients (Wang et al., 2020b).
T726 123552-123734 Sentence denotes Together, these studies unequivocally show heightened proinflammatory cytokine and chemokine response in circulation as well as at the site of infection in severe and critical cases.
T727 123735-123979 Sentence denotes Since these initial reports, all the subsequent studies revealed a consistent increase in IL-6, and to some extent TNF-α (Chen G. et al., 2020; Diao et al., 2020; Luo et al., 2020; Qin et al., 2020; Tan M. et al., 2020c; Zheng M. et al., 2020).
T728 123980-124240 Sentence denotes Based on the clinical cytokine profile across the studies in critical/deceased patients, serum IL-6 level is well established as a reliable predictive marker for COVID-19 severity and a potential marker of ARDS along with increased neutrophil/lymphocyte ratio.
T729 124241-124425 Sentence denotes Thus, considering a robust increase in IL-6 levels in the majority of the severe COVID-19 patients, currently, treatments are underway to lower the levels of this pleiotropic cytokine.
T730 124426-124593 Sentence denotes For example, antibodies directed against IL-6R (such as tocilizumab) have shown promising clinical outcomes (Capra et al., 2020; Luo et al., 2020; Xu X. et al., 2020).
T731 124594-124757 Sentence denotes Similarly, antibodies directed against GM-CSF (NCT04351243) and IL-β (NCT04348448) are also being explored for their efficacy to attenuate CS in COVID-19 patients.
T732 124758-124904 Sentence denotes A detailed list of the recent papers which reported clinical profiles of these inflammatory molecules in COVID-19 patients is provided in Table 1.
T733 124905-125045 Sentence denotes TABLE 1 List of some research articles from December 2019 to May 2020 establishing lymphocytopenia and cytokine storm in COVID-19 patients.
T734 125046-125048 Sentence denotes S.
T735 125049-125102 Sentence denotes No No. of patients Findings Sample References
T736 125103-125105 Sentence denotes 1.
T737 125107-125113 Sentence denotes Total:
T738 125114-125122 Sentence denotes 40 Mild:
T739 125123-125133 Sentence denotes 27 Severe:
T740 125134-125542 Sentence denotes 13 • Decrease in CD8+ and CD4+ T cell counts were observed suggesting lymphocytopenia• Increase in IL-2, IL-6, IL-10, and IFN-γ levels in severe cases• No significant changes were observed in IL-4 and TNF-α levels• The number of T cells increased in patients who recovered from the disease, along with a decrease in the cytokine levels comparable to mild cases Peripheral blood/Serum (Liu J. et al., 2020)
T741 125543-125545 Sentence denotes 2.
T742 125547-125553 Sentence denotes Total:
T743 125554-125574 Sentence denotes 147 Healthy control:
T744 125575-125592 Sentence denotes 45 Mild/moderate:
T745 125593-125603 Sentence denotes 42 Severe:
T746 125604-125616 Sentence denotes 43 Critical:
T747 125617-125956 Sentence denotes 17 • Increased levels of serum cytokines like TNF-α, IFN-γ, IL-2, IL-4, IL-6 and IL-10 were found in all COVID-19 patients• Similarly, CRP levels were increased in all COVID-19 patients, which showed positive correlation with IL-10• IL-6 and IL-10 levels were suggested as predictive disease severity biomarkers Serum (Han et al., 2020)
T748 125957-125959 Sentence denotes 3.
T749 125961-125979 Sentence denotes Total:138 Non-ICU:
T750 125980-125988 Sentence denotes 102 ICU:
T751 125989-126288 Sentence denotes 32 • Ninety-seven patients from both the groups showed lymphocytopenia.• Neutrophil count was significantly higher in ICU patients.• ICU patients showed significantly elevated levels of D-dimer, creatine kinase–MB, LD, ALT, AST, and procalcitonin suggesting multiple organ dysfunction in ICU cases.
T752 126290-126336 Sentence denotes Peripheral blood/Serum (Wang D. et al., 2020)
T753 126337-126339 Sentence denotes 4.
T754 126341-126361 Sentence denotes Total:191 Recovered:
T755 126362-126375 Sentence denotes 137 Deceased:
T756 126376-126450 Sentence denotes 58 • Deceased patients had lower levels of lymphocyte and platelet count.
T757 126451-126766 Sentence denotes Whereas higher levels of ALT, LDH, creatinine, creatinine kinase, troponin I, Serum ferritin, and D-dimer was observed in deceased patients’ samples• d-DIMER was suggested as a potential marker for COVID-19 severity• Higher IL-6 levels were found in deceased patients Peripheral blood/Serum (Zhou F. et al., 2020)
T758 126767-126769 Sentence denotes 5.
T759 126771-126788 Sentence denotes Total:41 Non-ICU:
T760 126789-126796 Sentence denotes 28 ICU:
T761 126797-127157 Sentence denotes 13 • Decrease in total lymphocyte count while increase in neutrophil count was observed in ICU patients.• Higher plasma levels of IL-2, IL-7, IL-10, GCSF, IP-10 (CXCL10), CCL2, CCL3, and TNF-α were observed in ICU patients as compared to non-ICU.• Increased levels of TH2 cytokine IL-4 was reported.• Increased levels of D-dimer, ALT, and AST in ICU patients.
T762 127159-127206 Sentence denotes Peripheral blood/Serum (Huang C. et al., 2020)
T763 127207-127209 Sentence denotes 6.
T764 127211-127231 Sentence denotes Total:150 Recovered:
T765 127232-127244 Sentence denotes 82 Deceased:
T766 127245-127471 Sentence denotes 68 • Increased levels of absolute lymphocyte count.• Significantly increased levels of IL-6, blood creatinine, myoglobin, cardiac troponin, CRP, total bilirubin, and blood urea nitrogen were observed in the deceased patients.
T767 127472-127561 Sentence denotes Further, higher levels of ALT, AST, LDH, creatinine, and creatinine kinase were observed.
T768 127563-127606 Sentence denotes Peripheral blood/Serum (Ruan et al., 2020)
T769 127607-127609 Sentence denotes 7.
T770 127611-127629 Sentence denotes Total:50 moderate:
T771 127630-127640 Sentence denotes 14 Severe:
T772 127641-127659 Sentence denotes 25 Critically ill:
T773 127660-128143 Sentence denotes 11 • Total percentage CD4+ T and CD8+ T cells was significantly lower in the severe cases along with increase in total neutrophil percentage, indicating overall dysfunctional immune response.• Increased levels of IFN-γ, IL-1ra, IL-2ra, IL-6, IL-10, IL-18, HGF, CCL7, MIG, M-CSF, G-CSF, MIG-1a, CTACK, and IP-10.• IP-10, CCL7, and IL-1RA were higher in severe cases compared to moderate.• Lymphocytopenia and increased neutrophil count was suggested to correlate with disease severe.
T774 128145-128191 Sentence denotes Peripheral blood/Serum (Yang Y. et al., 2020)
T775 128192-128194 Sentence denotes 8.
T776 128196-128214 Sentence denotes Total:21 moderate:
T777 128215-128610 Sentence denotes 10 Severe:11 • Absolute count of lymphocytes was decreased and specifically levels of CD4+ T and CD8+ T were lower in severe cases.• Higher levels of IL-2R, IL-6, IL-10, and TNF-α were observed in severe cases.• Higher levels of ALT, LDH, CRP, ferritin, and D-dimer was detected in severe cases.• Further, levels of IFN-γ levels specifically measured in CD4+ T cells were lower in severe cases.
T778 128612-128658 Sentence denotes Peripheral blood/Serum (Chen G. et al., 2020)
T779 128659-128661 Sentence denotes 9.
T780 128663-128762 Sentence denotes Total:1 deceased • CD4+ T and CD8+ T cells were reduced, however, they exhibited activated status.
T781 128763-128935 Sentence denotes Higher cytotoxic granules in CD8+ T cells indicated overactivation.• Increased levels of TH17 cells.• Inflammatory mononuclear infiltrates were observed in the lung tissue.
T782 128937-128981 Sentence denotes Peripheral blood/Serum (Xu Z. et al., 2020)
T783 128982-128985 Sentence denotes 10.
T784 128987-128993 Sentence denotes Total:
T785 128994-129009 Sentence denotes 452 Non-Severe:
T786 129010-129021 Sentence denotes 166 Severe:
T787 129022-129087 Sentence denotes 286 • The total number of T cells were decreased in severe case.
T788 129088-129264 Sentence denotes Further lower levels of CD4+ regulatory and CD8+ suppressor T cells was observed in severe cases.• Severe cases exhibited higher neutrophil counts and an increase in NLR ratio.
T789 129265-129478 Sentence denotes Whereas blood monocytes and eosinophil counts were lower.• Among the proinflammatory markers, increased levels of TNF-α, IL-2R, and IL-6, IL-8, IL-10 along with CRP, serum ferritin, and procalcitonin was observed.
T790 129479-129532 Sentence denotes Whereas no significant difference in IL-1β was found.
T791 129534-129576 Sentence denotes Peripheral blood/Serum (Qin et al., 2020)
T792 129577-129580 Sentence denotes 11.
T793 129582-129588 Sentence denotes Total:
T794 129589-129606 Sentence denotes 56 Mild/Moderate:
T795 129607-129616 Sentence denotes 31 Sever:
T796 129617-129706 Sentence denotes 25 • The levels of CD4+, CD8+ T cells, NK cells, and B cells were lower in severe cases.
T797 129707-129854 Sentence denotes Whereas, TREG cells were found to be moderately increased in mild cases.• Higher levels of IL-2, IL-6, IL-10, and TNF-α were found in severe cases.
T798 129855-129914 Sentence denotes Increase in IL-4 was observed in mild but not severe cases.
T799 129915-130079 Sentence denotes Further, IL-2 and IL-6 were suggested as reliable indicators for disease severity.• Serum leves were inconsistent with low levels or unchanged in COVID-19 patients.
T800 130081-130127 Sentence denotes Peripheral blood/Serum (Tan M. et al., 2020c)
T801 130128-130131 Sentence denotes 12.
T802 130133-130139 Sentence denotes Total:
T803 130140-130155 Sentence denotes 222 Non-severe:
T804 130156-130166 Sentence denotes 81 Severe:
T805 130167-130333 Sentence denotes 67 • Higher NLR with lower levels of CD4+, CD8+ T cells in severe cases.• Higher cytokine levels of IFN-γ, IL-2, IL-6, and IL-10 was found in patients with high NLR.
T806 130334-130522 Sentence denotes No significant difference in IL-4 levels were observed between severe and non-severe cases.• NLR was suggested as a predictive disease marker Peripheral blood/Serum (Zhang et al., 2020a)
T807 130523-130526 Sentence denotes 13.
T808 130528-130534 Sentence denotes Total:
T809 130535-130548 Sentence denotes 25 Recovered:
T810 130549-130566 Sentence denotes 14 Non-recovered:
T811 130567-130685 Sentence denotes 11 • Lower levels of CD3+ T cells, CD4+ T cells, CD8+ T, NK cells as well as B cells were found in COVID-19 patients.
T812 130686-130923 Sentence denotes Treated patients who exhibited clearance of virus showed restoration in levels of CD3+ T cells, CD4+ T cells, CD8+ T cells, whereas NK cell count was inconsistent.• Lymphocytopenia was considered as predicative biomarker for the disease.
T813 130925-130965 Sentence denotes Peripheral blood (Chen X. et al., 2020)
T814 130966-130969 Sentence denotes 14.
T815 130971-130977 Sentence denotes Total:
T816 130978-130989 Sentence denotes 22 Healthy:
T817 130990-131007 Sentence denotes 10 Mild/Moderate:
T818 131008-131018 Sentence denotes 10 Severe:
T819 131019-131176 Sentence denotes 6 • Marked reduction in functional CD4+ T cells was observed, as revealed by decrease in IFN-γ, and TNF-α produced by these cells in severe group than mild.
T820 131177-131535 Sentence denotes CD8+ T cells revealed activation profile as marked by increased levels of granzyme B and perforin in severe than mild cases.• CD8+ cells had increased expression of exhaustion marker CTLA-4 in severe than mild and increased PD-1 in mild than healthy group.• No significant differences in IL-6 and TNF-α was observed between severe, mild and healthy controls.
T821 131536-131578 Sentence denotes However, an increasing trend was observed.
T822 131580-131629 Sentence denotes Peripheral blood/Serum (Zheng H.Y. et al., 2020)
T823 131630-131633 Sentence denotes 15.
T824 131635-131641 Sentence denotes Total:
T825 131642-131659 Sentence denotes 68 Mild/Moderate:
T826 131660-131670 Sentence denotes 55 Severe:
T827 131671-131916 Sentence denotes 13 • Decreased number of CD8+ T and NK cells in patients showing severe symptoms.• Decrease in expression of IFN-γ, IL-2, granzyme-B by CD8+ T, and decrease in TNF-α expression by NK cells was observed, indicating CD8+ T and NK cell exhaustion.
T828 131918-131965 Sentence denotes Peripheral blood/Serum (Zheng M. et al., 2020)
T829 131966-131969 Sentence denotes 16.
T830 131971-131977 Sentence denotes Total:
T831 131978-132307 Sentence denotes 99 patients with mild to severe symptoms • Decrease in lymphocyte count and increase in neutrophils was observed when compared to the normal range.• Increased serum levels of IL-6, D-dimer, ALT, AST, LDH, Myoglobin, Procalcitonin, Serum ferritin, Erythrocyte sedimentation rate, and CRP was observed in all the studied patients.
T832 132308-132374 Sentence denotes Serum creatinine, and creatinine kinase showed inconsistent trend.
T833 132376-132422 Sentence denotes Peripheral blood/Serum (Chen N. et al., 2020)
T834 132423-132426 Sentence denotes 17.
T835 132428-132434 Sentence denotes Total:
T836 132435-132453 Sentence denotes 522 Mild/moderate:
T837 132454-132465 Sentence denotes 151 Severe:
T838 132466-132787 Sentence denotes 53 • Decreased number of total CD4+ and CD8+ T cells were observed in most of the patients with further decrease reported in patients who were admitted to ICU.• T cell exhaustion markers like PD1 and TIM3 were higher in severe disease patients.• Serum levels of TNF-α, IL-6 and IL-10 were higher in symptomatic patients.
T839 132788-133013 Sentence denotes However, no significant changes in the levels of IFN-γ, IL-2, and IL-4 were observed across groups.• T cell count restored and levels of IFN-γ, IL-10, IL-6, and TNF-α decreased as the disease resolved in a subset of patients.
T840 133015-133058 Sentence denotes Peripheral blood/Serum (Diao et al., 2020)
T841 133059-133062 Sentence denotes 18.
T842 133064-133070 Sentence denotes Total:
T843 133071-133084 Sentence denotes 710 Survivor:
T844 133085-133102 Sentence denotes 20 Non-survivors:
T845 133103-133215 Sentence denotes 32 • Blood analysis of non-survivors revealed decreased total lymphocyte count, and increase in platelet count.
T846 133216-133307 Sentence denotes Serum analysis revealed increase in total bilirubin, creatinine, and lactate concentration.
T847 133309-133355 Sentence denotes Peripheral blood/Serum (Yang X. et al., 2020)
T848 133356-133359 Sentence denotes 19.
T849 133361-133367 Sentence denotes Total:
T850 133368-133562 Sentence denotes 34 patients with varying disease severity • Presence of increased levels of inflammatory monocytes in the blood which were found to secrete proinflammatory cytokines like IL-10, IL6, and TNF-α.
T851 133564-133611 Sentence denotes Peripheral blood/Serum (Zhang D. et al., 2020)
T852 133612-133615 Sentence denotes 20.
T853 133617-133637 Sentence denotes Total:80 Non-severe:
T854 133638-133648 Sentence denotes 11 Severe:
T855 133649-133867 Sentence denotes 69 • The levels of CRP, ferritin, IL-6 and LDH were shown to be associated with longer treatment modality.• IL-6 levels were shown to positively correlate with disease severity and suggested as a predictive biomarker.
T856 133869-133897 Sentence denotes Serum (Liu T. et al., 2020)
T857 133898-133901 Sentence denotes 21.
T858 133903-133920 Sentence denotes Total:36 Healthy:
T859 133921-133932 Sentence denotes 10 Non-ICU:
T860 133933-133940 Sentence denotes 16 ICU:
T861 133941-134073 Sentence denotes 10 • Significant decrease in total lymphocytes including CD4+ and CD8+ T cells was observed in ICU patients as compared to non-ICU.
T862 134074-134131 Sentence denotes Both CD4+ and CD8+ T cells exhibited activated phenotype.
T863 134132-134343 Sentence denotes However, no changes were observed in B cells and NK cells between ICU and non-ICU patients.• Higher percentage of inflammatory monocytes were detected in COVID-19 patients, with further increase in ICU patients.
T864 134344-134415 Sentence denotes These monocytes were shown to secrete higher levels of GM-CSF and IL-6.
T865 134417-134455 Sentence denotes Peripheral blood (Zhou et al., 2020a)
T866 134456-134459 Sentence denotes 22.
T867 134461-134481 Sentence denotes Total:799 Recovered:
T868 134482-134495 Sentence denotes 161 Deceased:
T869 134496-134572 Sentence denotes 113 • Leukocytosis was observed in 56 patients who died due to the disease.
T870 134573-134930 Sentence denotes Deceased patients had robust decrease in lymphocytes and displayed lymphocytopenia.• Levels of IL-2, IL-6, IL-8, IL-10, and TNF-α were higher in deceased as compared to the recovered patients.• Serum levels of D-dimer, ferritin, ALT, AST, procalcitonin, creatinine creatine kinase, total bilirubin, ALP, and GGT were markedly increased in deceased patients.
T871 134932-134978 Sentence denotes Peripheral blood/Serum (Chen T. et al., 2020)
T872 134979-134982 Sentence denotes 23.
T873 134984-134990 Sentence denotes Total:
T874 134991-135010 Sentence denotes 70 Moderate- cured:
T875 135011-135027 Sentence denotes 40 Severe-cured:
T876 135028-135037 Sentence denotes 15 Death:
T877 135038-135133 Sentence denotes 15 • Robust decline in lymphocyte percentage in blood of patients who died due to the disease.
T878 135134-135338 Sentence denotes Whereas, substantial recovery of the blood lymphocyte percentage was seen in the patients who recovered from the disease.• The study suggests lymphocytopenia as a predictive prognosis marker for COVID-19.
T879 135340-135380 Sentence denotes Peripheral blood (Tan L. et al., 2020b)
T880 135381-135384 Sentence denotes 24.
T881 135386-135392 Sentence denotes Total:
T882 135393-135410 Sentence denotes 70 Mild/Moderate:
T883 135411-135422 Sentence denotes 8 Critical:
T884 135423-135434 Sentence denotes 10 Control:
T885 135435-135649 Sentence denotes 10 • Serum levels of CCL5 was highly increased in critically ill patients as compared to mild/moderate and healthy control.• Levels of IL-1β, IL-6, IL-8, and other chemokines CXCL8, CCL4, CCL3 were also increased.
T886 135651-135682 Sentence denotes Serum (Patterson et al., 2020)
T887 135683-135686 Sentence denotes 25.
T888 135688-135694 Sentence denotes Total:
T889 135695-135712 Sentence denotes 54 Mild/Moderate:
T890 135713-135723 Sentence denotes 26 Severe:
T891 135724-135982 Sentence denotes 28 • Macrophage activation syndrome along with hyperactivation of monocytes was found in severe cases.• Decrease in lymphocyte number (CD4+T and B cells) along with decline in NK cells was observed.• Blood IL-6 and CRP levels were increased in severe cases.
T892 135983-136071 Sentence denotes Further, increased levels of fibrinogen, D-dimers, creatinine was found in severe cases.
T893 136073-136134 Sentence denotes Peripheral blood/Serum (Giamarellos-Bourboulis et al., 2020)
T894 136135-136138 Sentence denotes 26.
T895 136140-136146 Sentence denotes Total:
T896 136147-136170 Sentence denotes 48 SARS-CoV-2 positive:
T897 136171-136194 Sentence denotes 24 SARS-CoV-2 negative:
T898 136195-136487 Sentence denotes 24 • Reduced IFN-I and IFN-III response was observed in patient samples as well as in in-vitro cell culture model of primary respiratory epithelial cells.• Increase in serum levels of IL-6, IL1RA, CCL2, CCL8 CXCL2, CXCL8, CXCL9, and CXCL16 were observed in Serum (Blanco-Melo et al., 2020)
T899 136488-136491 Sentence denotes 27.
T900 136493-136502 Sentence denotes COVID-19:
T901 136503-136516 Sentence denotes 1484 Healthy:
T902 136517-136526 Sentence denotes 9 Others:
T903 136527-136825 Sentence denotes 272 • Significantly higher levels of IL-6, IL-8, and TNF-α were observed in serum of COVID-19 patients as compared to the healthy control or patients with multiple myeloma.• IL-6, IL-8, and TNF-α were associated with worst disease outcome and suggested as the predictive indicators of the disease.
T904 136827-136858 Sentence denotes Serum (Del Valle et al., 2020)
T905 136859-136862 Sentence denotes 28.
T906 136864-136870 Sentence denotes Total:
T907 136871-136884 Sentence denotes 102 COVID-19:
T908 136885-136892 Sentence denotes 27 Flu:
T909 136893-137076 Sentence denotes 75 • COVID-19 patients showed increased levels of serum CRP, which was associated with disease progression.• CRP levels were suggested as a predictive marker in early stage COVID-19.
T910 137078-137106 Sentence denotes Serum (Tan C. et al., 2020)
T911 137107-137110 Sentence denotes 29.
T912 137112-137118 Sentence denotes Total:
T913 137119-137137 Sentence denotes 132 Mild/moderate:
T914 137138-137148 Sentence denotes 60 Severe:
T915 137149-137161 Sentence denotes 56 Critical:
T916 137162-137247 Sentence denotes 16 • Decreased lymphocyte number was observed in severe and critically ill patients.
T917 137248-137389 Sentence denotes Similarly, increased levels of serum CRP and SAA was observed.• SAA along with lymphocytopenia was suggested as a predicative disease marker.
T918 137391-137435 Sentence denotes Peripheral blood/Serum (Li H. et al., 2020)
T919 137436-137439 Sentence denotes 30.
T920 137441-137447 Sentence denotes Total:
T921 137448-137466 Sentence denotes 377 Mild/moderate:
T922 137467-137478 Sentence denotes 260 Severe:
T923 137479-137677 Sentence denotes 117 • Increased NLR, along with increased levels of serum CRP and D-dimer were observed in patients with severe disease symptoms.• NLT, CRP and d-DIMER were suggested as predictive disease markers.
T924 137679-137723 Sentence denotes Peripheral blood/Serum (Zhou et al., 2020b)
T925 137724-137727 Sentence denotes 31.
T926 137729-137735 Sentence denotes Total:
T927 137736-137754 Sentence denotes 377 Mild/moderate:
T928 137755-137765 Sentence denotes 69 Severe:
T929 137766-137864 Sentence denotes 24 • Significantly higher NLR, PLR, LMR, and total neutrophil count was observed in severe cases.
T930 137865-138012 Sentence denotes Whereas, the count of lymphocytes was decreased.• Serum CRP levels were higher in severe cases.• NLR was suggested as predictive disease biomarker.
T931 138014-138056 Sentence denotes Peripheral blood (Yang A.P. et al., 2020)
T932 138057-138060 Sentence denotes 32.
T933 138062-138068 Sentence denotes Total:
T934 138069-138079 Sentence denotes 18 Severe:
T935 138080-138092 Sentence denotes 16 Critical:
T936 138093-138453 Sentence denotes 2 • Increased activation profile of CD4+, CD8+ and plasmablasts was seen in COVID-19 patients.• Interestingly severe cases were associated with activated profile of CD4+ T cells, lower number of TFH cells and exhaustive CD8+ T cells.• Increased levels of serum AST, CRP, and creatinine kinase was observed.• CRP was suggested as the predictive disease marker.
T937 138455-138501 Sentence denotes Peripheral blood/Serum (Wang G. et al., 2020)
T938 138502-138505 Sentence denotes 33.
T939 138507-138513 Sentence denotes Total:
T940 138514-138525 Sentence denotes 221 Normal:
T941 138526-138539 Sentence denotes 36 Recovered:
T942 138540-138552 Sentence denotes 60 COVID-19:
T943 138553-139109 Sentence denotes 125 • CD4+ and CD8+ T cells were associated with the expression of activation markers (CD38 and HLA-DR), proliferation markers (Ki-67), and exhaustion markers (PD-1).• This elaborate study characterized 200 immune parameters and correlated with clinical features and disease severity.• Increase in chemokines like CXCL10, CXCL9, CCL2, and IL-1RA were observed in half of the COVID-19 patients.• Increased levels of ferritin, D-dimer, and CRP were observed in COVID-19 patients as compared to healthy controls or recovered patients. (Mathew et al., 2020)
T944 139110-139113 Sentence denotes 34.
T945 139115-139121 Sentence denotes Total:
T946 139122-139130 Sentence denotes 41 Mild:
T947 139131-139141 Sentence denotes 29 Severe:
T948 139142-139478 Sentence denotes 12 • Slight lymphocytopenia was observed in mild patients and significantly higher in severe COVID-19 patients as revealed by decrease in CD4+, CD8+ and NK cell number.• Peripheral blood showed increased activation status of CD8+ T with higher percentage of CD38+CD8+, CD38+HLA-DR, and CD38+HLA-DR+CD8+ cells in severe than mild cases.
T949 139479-139780 Sentence denotes While no significant changes were seen in CD4+• Increased expression of exhaustion markers PD-1 and TIM-3 was observed in CD8+, and PD-1 in CD4+ T cells in case of severe cases than mild.• Increased levels of IL-6, TNF-α, IL-17A, IFN-γ, MCP-1, IL-10, IL-4, and IL-5 were observed in COVID-19 patients.
T950 139782-139819 Sentence denotes Peripheral blood (Song et al., 2020)
T951 139820-139823 Sentence denotes 35.
T952 139825-139831 Sentence denotes Total:
T953 139832-140037 Sentence denotes 82 (deceased) • Lymphopenia, neutrophilia, and thrombocytopenia was observed.• Increased levels of CRP, LDH, ALT, and D-dimer were found.• Increased levels of IL-6 Peripheral blood (Zhang et al., 2020b)
T954 140038-140041 Sentence denotes 36.
T955 140043-140057 Sentence denotes Total:24 Mild:
T956 140058-140067 Sentence denotes 4 Severe:
T957 140068-140079 Sentence denotes 5 Critical:
T958 140080-140311 Sentence denotes 3 • Innate immune cells like monocytes, NK cells and myeloid-derived suppressor cells increased from mild to severe cases than declined in the critically ill patients.• CD8+ T cell subsets were decreased in all the disease groups.
T959 140312-140393 Sentence denotes However, CD4+ T, naïve CD4+ T, and TGF-β+CD28- naïve CD4+ T cells were increased.
T960 140394-140566 Sentence denotes On the contrary memory CD4+ T cells were decreased.• Levels of functional molecules such as CXCR3, CD28, and TGF-β were increased in patients as compared to health control.
T961 140568-140597 Sentence denotes PBMCs (Wang W. et al., 2020)
T962 140598-140601 Sentence denotes 37.
T963 140603-140609 Sentence denotes Total:
T964 140610-140622 Sentence denotes 53 Moderate:
T965 140623-140633 Sentence denotes 21 Severe:
T966 140634-140646 Sentence denotes 18 Critical:
T967 140647-140752 Sentence denotes 14 • CD11a expressing lymphocytes (CD4+ and CD8+) and B cells were decreased in critically ill patients.
T968 140753-140910 Sentence denotes Interestingly, it was suggested that T cell decline in circulation may be associated with increased infiltration of these cells toward the site of infection.
T969 140911-140978 Sentence denotes Whereas recovered patients showed reduced decline in CD11a T cells.
T970 140979-141149 Sentence denotes Thus, CD11a positive T cells were suggested as a possible prognostic marker of COVID-19.• Interestingly, eosinophil number was increased patients who were critically ill.
T971 141151-141177 Sentence denotes PBMCs (Anft et al., 2020)
T972 141178-141181 Sentence denotes 38.
T973 141183-141196 Sentence denotes BALF Healthy:
T974 141197-141208 Sentence denotes 3 Patients:
T975 141209-141225 Sentence denotes 2 PBMCs Healthy:
T976 141226-141237 Sentence denotes 3 Patients:
T977 141238-141469 Sentence denotes 3 • RNA-seq analysis was performed.• Increased transcript levels of IL-10, CCL2/MCP-1, CXCL10/IP-10, CCL3/MIP-1A, and CCL4/MIP1B in BALF.• Increased transcript levels of CXCL10, TNFSF10, TIMP1, C5, IL18, AREG, NRG1, IL10 in PBMCs.
T978 141471-141507 Sentence denotes PBMCs and BALF (Xiong et al., 2020)
T979 141508-141511 Sentence denotes 39.
T980 141513-141519 Sentence denotes Total:
T981 141520-141531 Sentence denotes 12 Healthy:
T982 141532-141543 Sentence denotes 3 Moderate:
T983 141544-141562 Sentence denotes 3 Severe/critical:
T984 141563-142287 Sentence denotes 6 • Single cell RNA-seq analysis was performed followed by cluster analysis to determine the immune cell type.• Proliferative and less expandable CD8+ T lymphocytes were present in severe/critically ill patient BALF samples, whereas moderate cases showed more expandable and less proliferative phenotype.• Increased macrophages and neutrophils were detected in the BALF of patients exhibiting severe/critical disease symptoms.• Higher levels of IL-1β, IL-6, and IL-8 were observed in all the patients.• Increased levels of CXCL9, CXCL10 and CXCL11 were consistently seen in all the patients.• Lung macrophages displayed higher transcripts of IL1B, IL6, TNFA, along with chemokines CCL2, CCL3, CCL4 and CCL7 in severe cases.
T985 142289-142314 Sentence denotes BALF (Liao et al., 2020)
T986 142315-142318 Sentence denotes 40.
T987 142320-142326 Sentence denotes Total:
T988 142327-142339 Sentence denotes 174 Healthy:
T989 142340-142352 Sentence denotes 20 COVID-19:
T990 142353-142362 Sentence denotes 8 Others:
T991 142363-142702 Sentence denotes 146 • Transcript levels of IL1RN, IL1B, CXCL17, CXCL8, CXCL1, CXCL2, and CCL2, CCL7 were increased in COVID-19 patients in comparison to healthy controls.• Upregulation of calgranulin genes S100A8, S100A9 and S100A12 were observed.• Interferon response was also observed as indicated by upregulation of about 83 ISGs in COVID-19 patients.
T992 142704-142732 Sentence denotes BALF (Zhou Z. et al., 2020)
T993 142733-142839 Sentence denotes The highlighted studies show the respective predictive biomarkers (in bold) which were found in the study.
T994 142841-142876 Sentence denotes Acute Respiratory Distress Syndrome
T995 142877-143078 Sentence denotes The consequences of the dysfunctional immune response as characterized by increased inflammatory cell infiltration, cytokine storm, and lymphocytopenia are the underlying concerns in COVID-19 patients.
T996 143079-143252 Sentence denotes This immunopathological state may eventually lead to the development of ARDS, which is associated with between 67 and 85% of ICU deaths (Ji et al., 2020; Liu et al., 2020b).
T997 143253-143386 Sentence denotes With a median time range from 8 to 12 days after symptom onset, ARDS progresses hierarchically during COVID-19 (Fan E. et al., 2020).
T998 143387-143576 Sentence denotes The late robust immune response generated by excessive infiltration of innate immune cells, proinflammatory cytokines, along with activated lymphocytes causes extensive damage to the lungs.
T999 143577-143759 Sentence denotes By this time, the injury incurred by the hyperactivated innate immune system far bypasses the damage by the virus, eventually leading to respiratory collapse and multi-organ failure.
T1000 143760-143986 Sentence denotes Taking cues from animal models and post-mortem samples of deceased SARS-CoV infected patients, a comprehensive picture of the clinical and molecular pattern of lung damage has emerged (Leung et al., 2005) as shown in Figure 5.
T1001 143987-144052 Sentence denotes These events proceed in a sequential and well-coordinated manner.
T1002 144053-144312 Sentence denotes Excessive alveolar epithelial cell death, loss of extracellular matrix, deposition of cellular debris, and formation of hyaline membrane starts early along with bronchiolar and alveolar epithelial cell denudation, referred to as diffuse alveolar damage (DAD).
T1003 144313-144562 Sentence denotes These events are proceeded by desquamation of the alveolar and bronchial epithelial lining, altered permeability of the alveolar-vascular barrier, interstitial pulmonary edema, thrombosis, coagulation, and fibrin deposition (Gralinski et al., 2013).
T1004 144563-144763 Sentence denotes Finally, the SARS-CoV disease progresses to a more severe fibrotic stage with increased fibroblast cell proliferation, interstitial fibrosis, collagen deposition, and complete collapse of the airways.
T1005 144764-144897 Sentence denotes The contents are released to the secondary tissues along with the proinflammatory cytokines, which may result in multi-organ failure.
T1006 144898-145047 Sentence denotes These changes are orchestrated by a coordinated action of molecular events that are ever-expanding (Chong et al., 2004; Jih, 2005; Yen et al., 2006).
T1007 145048-145281 Sentence denotes FIGURE 5 Immunopathological changes during different stages of COVID-19. (A) Immunological response in mild/moderate COVID-19 patients are overtly conferred by the adaptive immune cells with assistance from the innate immune system.
T1008 145282-145445 Sentence denotes Infected ATII cells and activated AMs produce a repertoire of cytokines and chemokines to recruit innate and adaptive immune cells and limit the viral propagation.
T1009 145446-145557 Sentence denotes The functional immune system thus acts in a well-coordinated manner to eliminate the virus specific ATII cells.
T1010 145558-145903 Sentence denotes Due to the relatively stem cell-like property of ATII cells, the eliminated cells are subsequently regenerated, thus ensuring recovery of the damaged lung tissue. (B) However, in severe/critically ill patients, an exaggerated inflammatory response is mounted by hyperactivated innate immune cells, and to a lower degree by adaptive immune cells.
T1011 145904-146087 Sentence denotes A hyperinflammatory state is created in the lungs which is characterized by the robust accumulation of inflammatory cells like monocytes/macrophages, dendritic cells, and neutrophils.
T1012 146088-146216 Sentence denotes This leads to the excessive release of cytokines and chemokines by these cells, thus inducing a vicious hyperinflammatory cycle.
T1013 146217-146358 Sentence denotes Damage to the lung parenchyma is inflicted by this hyperinflammatory state, along with other cytotoxic molecules like MMPs, NETs, ROS and NO.
T1014 146359-146424 Sentence denotes The latter two combine to form more cytotoxic peroxynitrite ions.
T1015 146425-146607 Sentence denotes The combined action of these events results in epithelial denudation, vascular leak, platelet and RBC infiltration, vascular edema, and hyaline membrane formation, resulting in ARDS.
T1016 146608-146698 Sentence denotes Recovery from ARDS is possible but only before the disease progresses to a critical stage.
T1017 146699-146854 Sentence denotes However, a mortality rate between 35 and 40% in ARDS patients demonstrates irreversible tissue damage manifested by tissue fibrosis (Bellani et al., 2016).
T1018 146855-146932 Sentence denotes TGF-β plays a central role in the late onset of fibrotic changes during ARDS.
T1019 146933-147194 Sentence denotes Acting with other proinflammatory molecules, TGF-β induces fibroblast cell proliferation and activation, collagen synthesis and deposition, synthesis of fibronectin, and alpha-smooth muscle actin, which all together contribute to fibrosis (Fan E. et al., 2020).
T1020 147195-147382 Sentence denotes Emerging histological studies from deceased COVID-19 patients reveal robust structural changes in the lungs and associated organs like the liver, kidneys, and heart (George et al., 2020).
T1021 147383-147639 Sentence denotes Lung biopsy samples from a 50-year-old patient who had succumbed to COVID-19 revealed hyaline membrane formation, desquamation of epithelial and endothelial cells, mononuclear infiltration, and robust ATII cell damage, indicating ARDS (Xu Z. et al., 2020).
T1022 147640-147762 Sentence denotes Further, microvesicular steatosis was observed in liver biopsy samples suggesting multi-organ damage (Xu Z. et al., 2020).
T1023 147763-148010 Sentence denotes Similarly, histopathological examination of a 72-year old patient who died due to SARS-CoV-2 infection revealed inflammatory infiltrates and fibrosis in the lungs along with intra-alveolar organizing fibrin suggesting ARDS (Zhang H. et al., 2020).
T1024 148011-148122 Sentence denotes In another study, lung samples from 38 deceased COVID-19 patients were evaluated for histopathological changes.
T1025 148123-148198 Sentence denotes Necrosis of alveolar epithelial cells and DAD was observed in all patients.
T1026 148199-148472 Sentence denotes While, most of the patients exhibited interstitial and intra-alveolar edema, ATII cell hyperplasia, thrombosis, fibrin deposition, infiltration of macrophages and lymphocytes, hyaline membrane formation and other fibrotic changes (Carsana et al., 2020; Polak et al., 2020).
T1027 148473-148561 Sentence denotes Similar histopathological findings were revealed by other studies (Menter et al., 2020).
T1028 148562-148672 Sentence denotes Clinical evaluation of 113 deceased patients revealed ARDS and multi-organ dysfunction (Chen T. et al., 2020).
T1029 148673-148923 Sentence denotes Increased serum concentration of molecular markers such as D-dimer, cardiac troponin creatinine, creatine kinase, alanine aminotransferase, aspartate aminotransferase, total bilirubin, alkaline phosphatase, and γ-glutamyl transpeptidase was observed.
T1030 148924-149002 Sentence denotes Presence of these molecules indicates damage to the liver, kidneys, and heart.
T1031 149003-149108 Sentence denotes Further, thrombosis and fibrinolysis were seen across the studies as revealed by elevated serum D-dimers.
T1032 149109-149399 Sentence denotes Besides, clinical evaluation of critically ill and deceased patients demonstrated elevated levels of biomolecules associated with damage to lungs, liver, kidneys, and heart, pointing to multi-organ dysfunction during COVID-19 (Chen T. et al., 2020; Huang C. et al., 2020; Zhu et al., 2020).
T1033 149400-149627 Sentence denotes It is emerging that ARDS in COVID-19 patients have a consistent presence of hyaline membrane, DAD, thrombosis and fibrotic changes, which may be the primary cause of ARDS-induced death (Fan E. et al., 2020; Price et al., 2020).
T1034 149628-149792 Sentence denotes Prospective longitudinal studies on clinical, molecular, and associated histopathological parameters will further delineate the molecular basis of ARDS in COVID-19.
T1035 149793-149916 Sentence denotes A list of studies that have detected D-dimers and associated clotting factors in COVID-19 patients is presented in Table 1.
T1036 149918-149937 Sentence denotes Future Perspectives
T1037 149938-150109 Sentence denotes Over the last several months, a large number of clinical and histological studies have illustrated the underlying pathophysiological changes and tissue damage in COVID-19.
T1038 150110-150244 Sentence denotes However, we are just beginning to understand the fundamental molecular and signaling pathways implicated in this disease pathogenesis.
T1039 150245-150497 Sentence denotes Close sequence similarity with SARS-CoV does help us understand some co-existing pathological features but owing to reasonable genomic and structural variations, and it is essential to decoding the molecular mechanisms specific to SARS-CoV-2 infection.
T1040 150498-150644 Sentence denotes Differences in S protein, ORF3b, ORF6 and ORF8 between SARS-CoV and SARS-CoV-2 are functionally relevant (Chan et al., 2020; Mantlo et al., 2020).
T1041 150645-150871 Sentence denotes Similarly, the differential immune responses generated by the two viruses needs to be delineated well to develop targeted therapies to modulate these specific molecular networks (Moreno-Eutimio et al., 2020; Yao et al., 2020).
T1042 150872-151085 Sentence denotes Importantly, heterogeneous T cell response in COVID-19 patients has remained an enigma, with lymphocytopenia and activated T cell state in some patients versus an increased presence of exhausted T cells in others.
T1043 151086-151342 Sentence denotes Further, the increased activation status of these cells at the site of infection (lungs) in severe cases adds more complexity to the T cell immune response in COVID-19 patients and hence may pose difficulty in devising a universal therapeutic intervention.
T1044 151343-151501 Sentence denotes Similarly, the presence of reactive T cells in healthy individuals is another area that needs a comprehensive understanding, mainly while designing a vaccine.
T1045 151502-151838 Sentence denotes Keeping these challenges in mind and till the time an effective vaccine becomes available, existing immunomodulatory approaches like mesenchymal stem cell-based therapies (currently under clinical trials), anti-IL6 and anti-GMCSF drugs to counter cytokine storm, as well as antiviral drugs remain the standard therapeutic interventions.
T1046 151839-151983 Sentence denotes While the antiviral drug remdesivir has shown promise in some patients, severe side effects were also reported in others (Wang Y. et al., 2020).
T1047 151984-152174 Sentence denotes Considering the number of factors that affect the complexity of immune response during COVID-19, it is crucial to understand that a single type of intervention may not work for all patients.
T1048 152175-152263 Sentence denotes Thus, it appears that exploring a combination therapy may be more compelling at present.
T1049 152264-152372 Sentence denotes However, determination of the optimal combination, dose, and time of treatment needs thorough investigation.
T1050 152373-152453 Sentence denotes These targeted therapies become critical, considering the chance of reinfection.
T1051 152454-152669 Sentence denotes A recent study on ten healthy individuals throughout 35-years revealed short-lasting immunity against four common seasonal coronaviruses, with chances of reinfection in a year after infection (Edridge et al., 2020).
T1052 152670-152800 Sentence denotes It is plausible that SARS-CoV-2 may exhibit the same tendency of reinfection, which may be a growing concern for vaccine research.
T1053 152801-152928 Sentence denotes Thus, a more comprehensive understanding of the immunopathological changes and sustainability of protective immunity is needed.
T1054 152929-153067 Sentence denotes In this review, we highlight some of these immunological responses, which are central to the progression and outcome of COVID-19 patients.
T1055 153068-153192 Sentence denotes Ongoing research in this direction should lead to effective therapies sooner rather than later, alongside with the vaccines.
T1056 153194-153214 Sentence denotes Author Contributions
T1057 153215-153291 Sentence denotes TA conceptualized the idea, generated the figures, and wrote the manuscript.
T1058 153292-153336 Sentence denotes RC helped in writing the immunology section.
T1059 153337-153389 Sentence denotes SA helped in designing and writing the ARDS section.
T1060 153390-153465 Sentence denotes MJ helped in writing the microbial nucleic acid-sensing and signaling part.
T1061 153466-153534 Sentence denotes AA ad AR helped in writing the innate immune response in SARS-CoV-2.
T1062 153535-153609 Sentence denotes All authors contributed to the article and approved the submitted version.
T1063 153611-153631 Sentence denotes Conflict of Interest
T1064 153632-153804 Sentence denotes The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
T1065 153806-153828 Sentence denotes Supplementary Material
T1066 153829-153987 Sentence denotes The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmicb.2020.588409/full#supplementary-material
T1067 153988-154024 Sentence denotes Click here for additional data file.
T1068 154026-154039 Sentence denotes Abbreviations
T1069 154040-154064 Sentence denotes ALP alkaline phosphatase
T1070 154065-154093 Sentence denotes ALT alanine aminotransferase
T1071 154094-154111 Sentence denotes AREG amphiregulin
T1072 154112-154142 Sentence denotes AST aspartate aminotransferase
T1073 154143-154176 Sentence denotes BALF bronchoalveolar Lavage Fluid
T1074 154177-154209 Sentence denotes CCL Chemokine (C-C motif) ligand
T1075 154210-154239 Sentence denotes CD cluster of differentiation
T1076 154240-154262 Sentence denotes CRP C-reactive protein
T1077 154263-154309 Sentence denotes CTACK (cutaneous T-cell -attracting chemokine)
T1078 154310-154345 Sentence denotes CXCL chemokine (C-X-C motif) ligand
T1079 154346-154389 Sentence denotes G-CSF Granulocyte colony-stimulating factor
T1080 154390-154420 Sentence denotes GGT γ -glutamyl transpeptidase
T1081 154421-154476 Sentence denotes GM-CSF Granulocyte-macrophage colony-stimulating factor
T1082 154477-154492 Sentence denotes IFN Interferons
T1083 154493-154508 Sentence denotes IL Interleukins
T1084 154509-154540 Sentence denotes ISG Interferon stimulating gene
T1085 154541-154565 Sentence denotes LD lactate dehydrogenase
T1086 154566-154591 Sentence denotes LDH Lactate dehydrogenase
T1087 154592-154624 Sentence denotes LMR lymphocyte-to-monocyte ratio
T1088 154625-154661 Sentence denotes MCP Monocyte Chemoattractant Protein
T1089 154662-154697 Sentence denotes MIP Macrophage Inflammatory Protein
T1090 154698-154715 Sentence denotes NK Natural killer
T1091 154716-154747 Sentence denotes NLR neutrophil/lymphocyte ratio
T1092 154748-154762 Sentence denotes NRG Neuregulin
T1093 154763-154801 Sentence denotes PBMC peripheral blood mononuclear cell
T1094 154802-154837 Sentence denotes PD1 Programmed cell death protein 1
T1095 154838-154870 Sentence denotes PLR platelet-to-lymphocyte ratio
T1096 154871-154892 Sentence denotes SP Surfactant protein
T1097 154893-154912 Sentence denotes SSA Serum Amyloid A
T1098 154913-154969 Sentence denotes TIM3 T-cell immunoglobulin and mucin-domain containing-3
T1099 154970-155014 Sentence denotes TIMP1 Tissue inhibitor of metalloproteinases
T1100 155015-155040 Sentence denotes TNF Tumor necrosis factor
T1101 155041-155105 Sentence denotes TNFSF10 (tumor necrosis factor (ligand) superfamily, member 10).