PMC:7647877 / 3765-17292 JSONTXT

{"project":"LitCovid-PD-FMA-UBERON","denotations":[{"id":"T27","span":{"begin":0,"end":13},"obj":"Body_part"},{"id":"T28","span":{"begin":45,"end":58},"obj":"Body_part"},{"id":"T29","span":{"begin":72,"end":82},"obj":"Body_part"},{"id":"T30","span":{"begin":239,"end":246},"obj":"Body_part"},{"id":"T31","span":{"begin":252,"end":265},"obj":"Body_part"},{"id":"T32","span":{"begin":467,"end":471},"obj":"Body_part"},{"id":"T33","span":{"begin":573,"end":586},"obj":"Body_part"},{"id":"T34","span":{"begin":605,"end":620},"obj":"Body_part"},{"id":"T35","span":{"begin":615,"end":620},"obj":"Body_part"},{"id":"T36","span":{"begin":622,"end":633},"obj":"Body_part"},{"id":"T37","span":{"begin":638,"end":649},"obj":"Body_part"},{"id":"T38","span":{"begin":684,"end":695},"obj":"Body_part"},{"id":"T39","span":{"begin":697,"end":707},"obj":"Body_part"},{"id":"T40","span":{"begin":702,"end":707},"obj":"Body_part"},{"id":"T41","span":{"begin":712,"end":732},"obj":"Body_part"},{"id":"T42","span":{"begin":727,"end":732},"obj":"Body_part"},{"id":"T43","span":{"begin":799,"end":812},"obj":"Body_part"},{"id":"T44","span":{"begin":871,"end":887},"obj":"Body_part"},{"id":"T45","span":{"begin":882,"end":887},"obj":"Body_part"},{"id":"T46","span":{"begin":894,"end":909},"obj":"Body_part"},{"id":"T47","span":{"begin":948,"end":956},"obj":"Body_part"},{"id":"T48","span":{"begin":984,"end":989},"obj":"Body_part"},{"id":"T49","span":{"begin":1051,"end":1061},"obj":"Body_part"},{"id":"T50","span":{"begin":1081,"end":1089},"obj":"Body_part"},{"id":"T51","span":{"begin":1139,"end":1147},"obj":"Body_part"},{"id":"T52","span":{"begin":1194,"end":1203},"obj":"Body_part"},{"id":"T53","span":{"begin":1205,"end":1215},"obj":"Body_part"},{"id":"T54","span":{"begin":1217,"end":1222},"obj":"Body_part"},{"id":"T55","span":{"begin":1279,"end":1290},"obj":"Body_part"},{"id":"T56","span":{"begin":1291,"end":1299},"obj":"Body_part"},{"id":"T57","span":{"begin":1323,"end":1336},"obj":"Body_part"},{"id":"T58","span":{"begin":1387,"end":1397},"obj":"Body_part"},{"id":"T59","span":{"begin":1399,"end":1410},"obj":"Body_part"},{"id":"T60","span":{"begin":1433,"end":1438},"obj":"Body_part"},{"id":"T61","span":{"begin":1454,"end":1470},"obj":"Body_part"},{"id":"T62","span":{"begin":1539,"end":1545},"obj":"Body_part"},{"id":"T63","span":{"begin":1547,"end":1554},"obj":"Body_part"},{"id":"T64","span":{"begin":1556,"end":1564},"obj":"Body_part"},{"id":"T65","span":{"begin":1566,"end":1577},"obj":"Body_part"},{"id":"T66","span":{"begin":1566,"end":1571},"obj":"Body_part"},{"id":"T67","span":{"begin":1582,"end":1612},"obj":"Body_part"},{"id":"T68","span":{"begin":1614,"end":1618},"obj":"Body_part"},{"id":"T69","span":{"begin":1689,"end":1700},"obj":"Body_part"},{"id":"T70","span":{"begin":1742,"end":1755},"obj":"Body_part"},{"id":"T71","span":{"begin":1760,"end":1773},"obj":"Body_part"},{"id":"T72","span":{"begin":1777,"end":1782},"obj":"Body_part"},{"id":"T73","span":{"begin":1788,"end":1801},"obj":"Body_part"},{"id":"T74","span":{"begin":1805,"end":1810},"obj":"Body_part"},{"id":"T75","span":{"begin":1833,"end":1838},"obj":"Body_part"},{"id":"T76","span":{"begin":1849,"end":1854},"obj":"Body_part"},{"id":"T77","span":{"begin":1858,"end":1863},"obj":"Body_part"},{"id":"T78","span":{"begin":1894,"end":1911},"obj":"Body_part"},{"id":"T79","span":{"begin":1906,"end":1911},"obj":"Body_part"},{"id":"T80","span":{"begin":1916,"end":1921},"obj":"Body_part"},{"id":"T81","span":{"begin":1924,"end":1938},"obj":"Body_part"},{"id":"T82","span":{"begin":1933,"end":1938},"obj":"Body_part"},{"id":"T83","span":{"begin":1961,"end":1966},"obj":"Body_part"},{"id":"T84","span":{"begin":2077,"end":2081},"obj":"Body_part"},{"id":"T85","span":{"begin":2101,"end":2115},"obj":"Body_part"},{"id":"T86","span":{"begin":2125,"end":2129},"obj":"Body_part"},{"id":"T87","span":{"begin":2204,"end":2228},"obj":"Body_part"},{"id":"T88","span":{"begin":2223,"end":2228},"obj":"Body_part"},{"id":"T89","span":{"begin":2236,"end":2251},"obj":"Body_part"},{"id":"T90","span":{"begin":2246,"end":2251},"obj":"Body_part"},{"id":"T91","span":{"begin":2323,"end":2355},"obj":"Body_part"},{"id":"T92","span":{"begin":2357,"end":2360},"obj":"Body_part"},{"id":"T93","span":{"begin":2448,"end":2453},"obj":"Body_part"},{"id":"T94","span":{"begin":2508,"end":2511},"obj":"Body_part"},{"id":"T95","span":{"begin":2534,"end":2545},"obj":"Body_part"},{"id":"T96","span":{"begin":2618,"end":2638},"obj":"Body_part"},{"id":"T97","span":{"begin":2663,"end":2672},"obj":"Body_part"},{"id":"T98","span":{"begin":2720,"end":2725},"obj":"Body_part"},{"id":"T99","span":{"begin":2743,"end":2754},"obj":"Body_part"},{"id":"T100","span":{"begin":2755,"end":2761},"obj":"Body_part"},{"id":"T101","span":{"begin":2756,"end":2758},"obj":"Body_part"},{"id":"T102","span":{"begin":2777,"end":2782},"obj":"Body_part"},{"id":"T103","span":{"begin":2851,"end":2860},"obj":"Body_part"},{"id":"T104","span":{"begin":2893,"end":2898},"obj":"Body_part"},{"id":"T105","span":{"begin":2893,"end":2895},"obj":"Body_part"},{"id":"T106","span":{"begin":2911,"end":2922},"obj":"Body_part"},{"id":"T107","span":{"begin":2954,"end":2962},"obj":"Body_part"},{"id":"T108","span":{"begin":2957,"end":2962},"obj":"Body_part"},{"id":"T109","span":{"begin":2999,"end":3001},"obj":"Body_part"},{"id":"T110","span":{"begin":3026,"end":3031},"obj":"Body_part"},{"id":"T111","span":{"begin":3033,"end":3042},"obj":"Body_part"},{"id":"T112","span":{"begin":3046,"end":3056},"obj":"Body_part"},{"id":"T113","span":{"begin":3051,"end":3056},"obj":"Body_part"},{"id":"T114","span":{"begin":3097,"end":3099},"obj":"Body_part"},{"id":"T115","span":{"begin":3104,"end":3106},"obj":"Body_part"},{"id":"T116","span":{"begin":3120,"end":3122},"obj":"Body_part"},{"id":"T117","span":{"begin":3171,"end":3176},"obj":"Body_part"},{"id":"T118","span":{"begin":3185,"end":3187},"obj":"Body_part"},{"id":"T119","span":{"begin":3195,"end":3197},"obj":"Body_part"},{"id":"T120","span":{"begin":3255,"end":3263},"obj":"Body_part"},{"id":"T121","span":{"begin":3285,"end":3297},"obj":"Body_part"},{"id":"T122","span":{"begin":3285,"end":3289},"obj":"Body_part"},{"id":"T123","span":{"begin":3457,"end":3464},"obj":"Body_part"},{"id":"T124","span":{"begin":3543,"end":3547},"obj":"Body_part"},{"id":"T125","span":{"begin":3715,"end":3719},"obj":"Body_part"},{"id":"T126","span":{"begin":3715,"end":3717},"obj":"Body_part"},{"id":"T127","span":{"begin":3721,"end":3723},"obj":"Body_part"},{"id":"T128","span":{"begin":3727,"end":3729},"obj":"Body_part"},{"id":"T129","span":{"begin":3733,"end":3735},"obj":"Body_part"},{"id":"T130","span":{"begin":3739,"end":3741},"obj":"Body_part"},{"id":"T131","span":{"begin":3746,"end":3748},"obj":"Body_part"},{"id":"T132","span":{"begin":3753,"end":3758},"obj":"Body_part"},{"id":"T133","span":{"begin":3753,"end":3755},"obj":"Body_part"},{"id":"T134","span":{"begin":3760,"end":3762},"obj":"Body_part"},{"id":"T135","span":{"begin":3767,"end":3769},"obj":"Body_part"},{"id":"T136","span":{"begin":3774,"end":3776},"obj":"Body_part"},{"id":"T137","span":{"begin":3781,"end":3783},"obj":"Body_part"},{"id":"T138","span":{"begin":3791,"end":3793},"obj":"Body_part"},{"id":"T139","span":{"begin":3807,"end":3817},"obj":"Body_part"},{"id":"T140","span":{"begin":3855,"end":3864},"obj":"Body_part"},{"id":"T141","span":{"begin":3922,"end":3926},"obj":"Body_part"},{"id":"T142","span":{"begin":3970,"end":3979},"obj":"Body_part"},{"id":"T143","span":{"begin":4010,"end":4018},"obj":"Body_part"},{"id":"T144","span":{"begin":4035,"end":4042},"obj":"Body_part"},{"id":"T145","span":{"begin":4091,"end":4099},"obj":"Body_part"},{"id":"T146","span":{"begin":4311,"end":4316},"obj":"Body_part"},{"id":"T147","span":{"begin":4392,"end":4401},"obj":"Body_part"},{"id":"T148","span":{"begin":4423,"end":4433},"obj":"Body_part"},{"id":"T149","span":{"begin":4520,"end":4534},"obj":"Body_part"},{"id":"T150","span":{"begin":4520,"end":4532},"obj":"Body_part"},{"id":"T151","span":{"begin":4536,"end":4540},"obj":"Body_part"},{"id":"T152","span":{"begin":4536,"end":4538},"obj":"Body_part"},{"id":"T153","span":{"begin":4547,"end":4549},"obj":"Body_part"},{"id":"T154","span":{"begin":4562,"end":4567},"obj":"Body_part"},{"id":"T155","span":{"begin":4562,"end":4564},"obj":"Body_part"},{"id":"T156","span":{"begin":4978,"end":4981},"obj":"Body_part"},{"id":"T157","span":{"begin":5005,"end":5008},"obj":"Body_part"},{"id":"T158","span":{"begin":5035,"end":5038},"obj":"Body_part"},{"id":"T159","span":{"begin":5062,"end":5073},"obj":"Body_part"},{"id":"T160","span":{"begin":5075,"end":5090},"obj":"Body_part"},{"id":"T161","span":{"begin":5085,"end":5090},"obj":"Body_part"},{"id":"T162","span":{"begin":5092,"end":5103},"obj":"Body_part"},{"id":"T163","span":{"begin":5105,"end":5116},"obj":"Body_part"},{"id":"T164","span":{"begin":5118,"end":5134},"obj":"Body_part"},{"id":"T165","span":{"begin":5129,"end":5134},"obj":"Body_part"},{"id":"T166","span":{"begin":5139,"end":5152},"obj":"Body_part"},{"id":"T167","span":{"begin":5251,"end":5254},"obj":"Body_part"},{"id":"T168","span":{"begin":5332,"end":5344},"obj":"Body_part"},{"id":"T169","span":{"begin":5447,"end":5457},"obj":"Body_part"},{"id":"T170","span":{"begin":5474,"end":5481},"obj":"Body_part"},{"id":"T171","span":{"begin":5500,"end":5508},"obj":"Body_part"},{"id":"T172","span":{"begin":5585,"end":5592},"obj":"Body_part"},{"id":"T173","span":{"begin":5797,"end":5809},"obj":"Body_part"},{"id":"T174","span":{"begin":5816,"end":5839},"obj":"Body_part"},{"id":"T175","span":{"begin":5827,"end":5839},"obj":"Body_part"},{"id":"T176","span":{"begin":5862,"end":5876},"obj":"Body_part"},{"id":"T177","span":{"begin":5878,"end":5880},"obj":"Body_part"},{"id":"T178","span":{"begin":5882,"end":5893},"obj":"Body_part"},{"id":"T179","span":{"begin":5895,"end":5898},"obj":"Body_part"},{"id":"T180","span":{"begin":5997,"end":6002},"obj":"Body_part"},{"id":"T181","span":{"begin":6008,"end":6027},"obj":"Body_part"},{"id":"T182","span":{"begin":6023,"end":6027},"obj":"Body_part"},{"id":"T183","span":{"begin":6033,"end":6052},"obj":"Body_part"},{"id":"T184","span":{"begin":6040,"end":6052},"obj":"Body_part"},{"id":"T185","span":{"begin":6187,"end":6196},"obj":"Body_part"},{"id":"T186","span":{"begin":6202,"end":6211},"obj":"Body_part"},{"id":"T187","span":{"begin":6283,"end":6292},"obj":"Body_part"},{"id":"T188","span":{"begin":6298,"end":6307},"obj":"Body_part"},{"id":"T189","span":{"begin":6309,"end":6313},"obj":"Body_part"},{"id":"T190","span":{"begin":6309,"end":6311},"obj":"Body_part"},{"id":"T191","span":{"begin":6315,"end":6317},"obj":"Body_part"},{"id":"T192","span":{"begin":6322,"end":6324},"obj":"Body_part"},{"id":"T193","span":{"begin":6489,"end":6502},"obj":"Body_part"},{"id":"T194","span":{"begin":6556,"end":6561},"obj":"Body_part"},{"id":"T195","span":{"begin":6563,"end":6565},"obj":"Body_part"},{"id":"T196","span":{"begin":6580,"end":6585},"obj":"Body_part"},{"id":"T197","span":{"begin":6587,"end":6589},"obj":"Body_part"},{"id":"T198","span":{"begin":6803,"end":6806},"obj":"Body_part"},{"id":"T199","span":{"begin":6906,"end":6914},"obj":"Body_part"},{"id":"T200","span":{"begin":7188,"end":7195},"obj":"Body_part"},{"id":"T201","span":{"begin":7228,"end":7245},"obj":"Body_part"},{"id":"T202","span":{"begin":7240,"end":7245},"obj":"Body_part"},{"id":"T203","span":{"begin":7253,"end":7264},"obj":"Body_part"},{"id":"T204","span":{"begin":7276,"end":7285},"obj":"Body_part"},{"id":"T205","span":{"begin":7293,"end":7298},"obj":"Body_part"},{"id":"T206","span":{"begin":7300,"end":7309},"obj":"Body_part"},{"id":"T207","span":{"begin":7311,"end":7316},"obj":"Body_part"},{"id":"T208","span":{"begin":7318,"end":7323},"obj":"Body_part"},{"id":"T209","span":{"begin":7328,"end":7334},"obj":"Body_part"},{"id":"T210","span":{"begin":7358,"end":7362},"obj":"Body_part"},{"id":"T211","span":{"begin":7432,"end":7436},"obj":"Body_part"},{"id":"T212","span":{"begin":7628,"end":7631},"obj":"Body_part"},{"id":"T213","span":{"begin":7659,"end":7669},"obj":"Body_part"},{"id":"T214","span":{"begin":7712,"end":7722},"obj":"Body_part"},{"id":"T215","span":{"begin":7778,"end":7785},"obj":"Body_part"},{"id":"T216","span":{"begin":8045,"end":8058},"obj":"Body_part"},{"id":"T217","span":{"begin":8574,"end":8581},"obj":"Body_part"},{"id":"T218","span":{"begin":8681,"end":8685},"obj":"Body_part"},{"id":"T219","span":{"begin":8829,"end":8846},"obj":"Body_part"},{"id":"T220","span":{"begin":8841,"end":8846},"obj":"Body_part"},{"id":"T221","span":{"begin":8880,"end":8889},"obj":"Body_part"},{"id":"T222","span":{"begin":9035,"end":9042},"obj":"Body_part"},{"id":"T223","span":{"begin":9079,"end":9085},"obj":"Body_part"},{"id":"T224","span":{"begin":9159,"end":9164},"obj":"Body_part"},{"id":"T225","span":{"begin":9563,"end":9567},"obj":"Body_part"},{"id":"T226","span":{"begin":9708,"end":9718},"obj":"Body_part"},{"id":"T227","span":{"begin":10059,"end":10070},"obj":"Body_part"},{"id":"T228","span":{"begin":10421,"end":10429},"obj":"Body_part"},{"id":"T229","span":{"begin":10565,"end":10570},"obj":"Body_part"},{"id":"T230","span":{"begin":10572,"end":10574},"obj":"Body_part"},{"id":"T231","span":{"begin":10588,"end":10593},"obj":"Body_part"},{"id":"T232","span":{"begin":10595,"end":10597},"obj":"Body_part"},{"id":"T233","span":{"begin":10626,"end":10634},"obj":"Body_part"},{"id":"T234","span":{"begin":10643,"end":10647},"obj":"Body_part"},{"id":"T235","span":{"begin":10643,"end":10645},"obj":"Body_part"},{"id":"T236","span":{"begin":10674,"end":10679},"obj":"Body_part"},{"id":"T237","span":{"begin":10754,"end":10779},"obj":"Body_part"},{"id":"T238","span":{"begin":10774,"end":10779},"obj":"Body_part"},{"id":"T239","span":{"begin":10798,"end":10809},"obj":"Body_part"},{"id":"T240","span":{"begin":10872,"end":10881},"obj":"Body_part"},{"id":"T241","span":{"begin":11040,"end":11050},"obj":"Body_part"},{"id":"T242","span":{"begin":11105,"end":11109},"obj":"Body_part"},{"id":"T243","span":{"begin":11105,"end":11107},"obj":"Body_part"},{"id":"T244","span":{"begin":11167,"end":11182},"obj":"Body_part"},{"id":"T245","span":{"begin":11184,"end":11195},"obj":"Body_part"},{"id":"T246","span":{"begin":11200,"end":11215},"obj":"Body_part"},{"id":"T247","span":{"begin":11210,"end":11215},"obj":"Body_part"},{"id":"T248","span":{"begin":11224,"end":11228},"obj":"Body_part"},{"id":"T249","span":{"begin":11224,"end":11226},"obj":"Body_part"},{"id":"T250","span":{"begin":11339,"end":11345},"obj":"Body_part"},{"id":"T251","span":{"begin":11354,"end":11364},"obj":"Body_part"},{"id":"T252","span":{"begin":11440,"end":11447},"obj":"Body_part"},{"id":"T253","span":{"begin":11679,"end":11683},"obj":"Body_part"},{"id":"T254","span":{"begin":11679,"end":11681},"obj":"Body_part"},{"id":"T255","span":{"begin":11696,"end":11700},"obj":"Body_part"},{"id":"T256","span":{"begin":11696,"end":11698},"obj":"Body_part"},{"id":"T257","span":{"begin":11771,"end":11775},"obj":"Body_part"},{"id":"T258","span":{"begin":11771,"end":11773},"obj":"Body_part"},{"id":"T259","span":{"begin":12013,"end":12015},"obj":"Body_part"},{"id":"T260","span":{"begin":12059,"end":12086},"obj":"Body_part"},{"id":"T261","span":{"begin":12146,"end":12160},"obj":"Body_part"},{"id":"T262","span":{"begin":12361,"end":12376},"obj":"Body_part"},{"id":"T263","span":{"begin":12916,"end":12924},"obj":"Body_part"},{"id":"T264","span":{"begin":12926,"end":12935},"obj":"Body_part"},{"id":"T265","span":{"begin":12945,"end":12956},"obj":"Body_part"}],"attributes":[{"id":"A27","pred":"fma_id","subj":"T27","obj":"http://purl.org/sig/ont/fma/fma9825"},{"id":"A28","pred":"fma_id","subj":"T28","obj":"http://purl.org/sig/ont/fma/fma9825"},{"id":"A29","pred":"fma_id","subj":"T29","obj":"http://purl.org/sig/ont/fma/fma305853"},{"id":"A30","pred":"fma_id","subj":"T30","obj":"http://purl.org/sig/ont/fma/fma9637"},{"id":"A31","pred":"fma_id","subj":"T31","obj":"http://purl.org/sig/ont/fma/fma9825"},{"id":"A32","pred":"fma_id","subj":"T32","obj":"http://purl.org/sig/ont/fma/fma9712"},{"id":"A33","pred":"fma_id","subj":"T33","obj":"http://purl.org/sig/ont/fma/fma9825"},{"id":"A34","pred":"fma_id","subj":"T34","obj":"http://purl.org/sig/ont/fma/fma273565"},{"id":"A35","pred":"fma_id","subj":"T35","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A36","pred":"fma_id","subj":"T36","obj":"http://purl.org/sig/ont/fma/fma63261"},{"id":"A37","pred":"fma_id","subj":"T37","obj":"http://purl.org/sig/ont/fma/fma62860"},{"id":"A38","pred":"fma_id","subj":"T38","obj":"http://purl.org/sig/ont/fma/fma62861"},{"id":"A39","pred":"fma_id","subj":"T39","obj":"http://purl.org/sig/ont/fma/fma66784"},{"id":"A40","pred":"fma_id","subj":"T40","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A41","pred":"fma_id","subj":"T41","obj":"http://purl.org/sig/ont/fma/fma63147"},{"id":"A42","pred":"fma_id","subj":"T42","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A43","pred":"fma_id","subj":"T43","obj":"http://purl.org/sig/ont/fma/fma9825"},{"id":"A44","pred":"fma_id","subj":"T44","obj":"http://purl.org/sig/ont/fma/fma66768"},{"id":"A45","pred":"fma_id","subj":"T45","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A46","pred":"fma_id","subj":"T46","obj":"http://purl.org/sig/ont/fma/fma67397"},{"id":"A47","pred":"fma_id","subj":"T47","obj":"http://purl.org/sig/ont/fma/fma61790"},{"id":"A48","pred":"fma_id","subj":"T48","obj":"http://purl.org/sig/ont/fma/fma66938"},{"id":"A49","pred":"fma_id","subj":"T49","obj":"http://purl.org/sig/ont/fma/fma9639"},{"id":"A50","pred":"fma_id","subj":"T50","obj":"http://purl.org/sig/ont/fma/fma67257"},{"id":"A51","pred":"fma_id","subj":"T51","obj":"http://purl.org/sig/ont/fma/fma67257"},{"id":"A52","pred":"fma_id","subj":"T52","obj":"http://purl.org/sig/ont/fma/fma84050"},{"id":"A53","pred":"fma_id","subj":"T53","obj":"http://purl.org/sig/ont/fma/fma241981"},{"id":"A54","pred":"fma_id","subj":"T54","obj":"http://purl.org/sig/ont/fma/fma67264"},{"id":"A55","pred":"fma_id","subj":"T55","obj":"http://purl.org/sig/ont/fma/fma66835"},{"id":"A56","pred":"fma_id","subj":"T56","obj":"http://purl.org/sig/ont/fma/fma67257"},{"id":"A57","pred":"fma_id","subj":"T57","obj":"http://purl.org/sig/ont/fma/fma9825"},{"id":"A58","pred":"fma_id","subj":"T58","obj":"http://purl.org/sig/ont/fma/fma62852"},{"id":"A59","pred":"fma_id","subj":"T59","obj":"http://purl.org/sig/ont/fma/fma62863"},{"id":"A60","pred":"fma_id","subj":"T60","obj":"http://purl.org/sig/ont/fma/fma9670"},{"id":"A61","pred":"fma_id","subj":"T61","obj":"http://purl.org/sig/ont/fma/fma7162"},{"id":"A62","pred":"fma_id","subj":"T62","obj":"http://purl.org/sig/ont/fma/fma7196"},{"id":"A63","pred":"fma_id","subj":"T63","obj":"http://purl.org/sig/ont/fma/fma9609"},{"id":"A64","pred":"fma_id","subj":"T64","obj":"http://purl.org/sig/ont/fma/fma14542"},{"id":"A65","pred":"fma_id","subj":"T65","obj":"http://purl.org/sig/ont/fma/fma5034"},{"id":"A66","pred":"fma_id","subj":"T66","obj":"http://purl.org/sig/ont/fma/fma9671"},{"id":"A67","pred":"fma_id","subj":"T67","obj":"http://purl.org/sig/ont/fma/fma62820"},{"id":"A68","pred":"fma_id","subj":"T68","obj":"http://purl.org/sig/ont/fma/fma62820"},{"id":"A69","pred":"fma_id","subj":"T69","obj":"http://purl.org/sig/ont/fma/fma62863"},{"id":"A70","pred":"fma_id","subj":"T70","obj":"http://purl.org/sig/ont/fma/fma9825"},{"id":"A71","pred":"fma_id","subj":"T71","obj":"http://purl.org/sig/ont/fma/fma62869"},{"id":"A72","pred":"fma_id","subj":"T72","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A73","pred":"fma_id","subj":"T73","obj":"http://purl.org/sig/ont/fma/fma62870"},{"id":"A74","pred":"fma_id","subj":"T74","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A75","pred":"fma_id","subj":"T75","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A76","pred":"fma_id","subj":"T76","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A77","pred":"fma_id","subj":"T77","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A78","pred":"fma_id","subj":"T78","obj":"http://purl.org/sig/ont/fma/fma70573"},{"id":"A79","pred":"fma_id","subj":"T79","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A80","pred":"fma_id","subj":"T80","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A81","pred":"fma_id","subj":"T81","obj":"http://purl.org/sig/ont/fma/fma70572"},{"id":"A82","pred":"fma_id","subj":"T82","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A83","pred":"fma_id","subj":"T83","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A84","pred":"fma_id","subj":"T84","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A85","pred":"fma_id","subj":"T85","obj":"http://purl.org/sig/ont/fma/fma62871"},{"id":"A86","pred":"fma_id","subj":"T86","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A87","pred":"fma_id","subj":"T87","obj":"http://purl.org/sig/ont/fma/fma273565"},{"id":"A88","pred":"fma_id","subj":"T88","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A89","pred":"fma_id","subj":"T89","obj":"http://purl.org/sig/ont/fma/fma273565"},{"id":"A90","pred":"fma_id","subj":"T90","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A91","pred":"fma_id","subj":"T91","obj":"http://purl.org/sig/ont/fma/fma84079"},{"id":"A92","pred":"fma_id","subj":"T92","obj":"http://purl.org/sig/ont/fma/fma84079"},{"id":"A93","pred":"fma_id","subj":"T93","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A94","pred":"fma_id","subj":"T94","obj":"http://purl.org/sig/ont/fma/fma84079"},{"id":"A95","pred":"fma_id","subj":"T95","obj":"http://purl.org/sig/ont/fma/fma62863"},{"id":"A96","pred":"fma_id","subj":"T96","obj":"http://purl.org/sig/ont/fma/fma70572"},{"id":"A97","pred":"fma_id","subj":"T97","obj":"http://purl.org/sig/ont/fma/fma84050"},{"id":"A98","pred":"fma_id","subj":"T98","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A99","pred":"fma_id","subj":"T99","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A100","pred":"fma_id","subj":"T100","obj":"http://purl.org/sig/ont/fma/fma84051"},{"id":"A101","pred":"fma_id","subj":"T101","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A102","pred":"fma_id","subj":"T102","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A103","pred":"fma_id","subj":"T103","obj":"http://purl.org/sig/ont/fma/fma84050"},{"id":"A104","pred":"fma_id","subj":"T104","obj":"http://purl.org/sig/ont/fma/fma86579"},{"id":"A105","pred":"fma_id","subj":"T105","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A106","pred":"fma_id","subj":"T106","obj":"http://purl.org/sig/ont/fma/fma63261"},{"id":"A107","pred":"fma_id","subj":"T107","obj":"http://purl.org/sig/ont/fma/fma63147"},{"id":"A108","pred":"fma_id","subj":"T108","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A109","pred":"fma_id","subj":"T109","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A110","pred":"fma_id","subj":"T110","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A111","pred":"fma_id","subj":"T111","obj":"http://purl.org/sig/ont/fma/fma62862"},{"id":"A112","pred":"fma_id","subj":"T112","obj":"http://purl.org/sig/ont/fma/fma66784"},{"id":"A113","pred":"fma_id","subj":"T113","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A114","pred":"fma_id","subj":"T114","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A115","pred":"fma_id","subj":"T115","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A116","pred":"fma_id","subj":"T116","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A117","pred":"fma_id","subj":"T117","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A118","pred":"fma_id","subj":"T118","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A119","pred":"fma_id","subj":"T119","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A120","pred":"fma_id","subj":"T120","obj":"http://purl.org/sig/ont/fma/fma84050"},{"id":"A121","pred":"fma_id","subj":"T121","obj":"http://purl.org/sig/ont/fma/fma67653"},{"id":"A122","pred":"fma_id","subj":"T122","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A123","pred":"fma_id","subj":"T123","obj":"http://purl.org/sig/ont/fma/fma67257"},{"id":"A124","pred":"fma_id","subj":"T124","obj":"http://purl.org/sig/ont/fma/fma74402"},{"id":"A125","pred":"fma_id","subj":"T125","obj":"http://purl.org/sig/ont/fma/fma84051"},{"id":"A126","pred":"fma_id","subj":"T126","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A127","pred":"fma_id","subj":"T127","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A128","pred":"fma_id","subj":"T128","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A129","pred":"fma_id","subj":"T129","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A130","pred":"fma_id","subj":"T130","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A131","pred":"fma_id","subj":"T131","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A132","pred":"fma_id","subj":"T132","obj":"http://purl.org/sig/ont/fma/fma86579"},{"id":"A133","pred":"fma_id","subj":"T133","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A134","pred":"fma_id","subj":"T134","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A135","pred":"fma_id","subj":"T135","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A136","pred":"fma_id","subj":"T136","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A137","pred":"fma_id","subj":"T137","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A138","pred":"fma_id","subj":"T138","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A139","pred":"fma_id","subj":"T139","obj":"http://purl.org/sig/ont/fma/fma241981"},{"id":"A140","pred":"fma_id","subj":"T140","obj":"http://purl.org/sig/ont/fma/fma241981"},{"id":"A141","pred":"fma_id","subj":"T141","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A142","pred":"fma_id","subj":"T142","obj":"http://purl.org/sig/ont/fma/fma241981"},{"id":"A143","pred":"fma_id","subj":"T143","obj":"http://purl.org/sig/ont/fma/fma62864"},{"id":"A144","pred":"fma_id","subj":"T144","obj":"http://purl.org/sig/ont/fma/fma67257"},{"id":"A145","pred":"fma_id","subj":"T145","obj":"http://purl.org/sig/ont/fma/fma62871"},{"id":"A146","pred":"fma_id","subj":"T146","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A147","pred":"fma_id","subj":"T147","obj":"http://purl.org/sig/ont/fma/fma84050"},{"id":"A148","pred":"fma_id","subj":"T148","obj":"http://purl.org/sig/ont/fma/fma241981"},{"id":"A149","pred":"fma_id","subj":"T149","obj":"http://purl.org/sig/ont/fma/fma86583"},{"id":"A150","pred":"fma_id","subj":"T150","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A151","pred":"fma_id","subj":"T151","obj":"http://purl.org/sig/ont/fma/fma86583"},{"id":"A152","pred":"fma_id","subj":"T152","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A153","pred":"fma_id","subj":"T153","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A154","pred":"fma_id","subj":"T154","obj":"http://purl.org/sig/ont/fma/fma86579"},{"id":"A155","pred":"fma_id","subj":"T155","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A156","pred":"fma_id","subj":"T156","obj":"http://purl.org/sig/ont/fma/fma74412"},{"id":"A157","pred":"fma_id","subj":"T157","obj":"http://purl.org/sig/ont/fma/fma67095"},{"id":"A158","pred":"fma_id","subj":"T158","obj":"http://purl.org/sig/ont/fma/fma67095"},{"id":"A159","pred":"fma_id","subj":"T159","obj":"http://purl.org/sig/ont/fma/fma63261"},{"id":"A160","pred":"fma_id","subj":"T160","obj":"http://purl.org/sig/ont/fma/fma273565"},{"id":"A161","pred":"fma_id","subj":"T161","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A162","pred":"fma_id","subj":"T162","obj":"http://purl.org/sig/ont/fma/fma62860"},{"id":"A163","pred":"fma_id","subj":"T163","obj":"http://purl.org/sig/ont/fma/fma62861"},{"id":"A164","pred":"fma_id","subj":"T164","obj":"http://purl.org/sig/ont/fma/fma66768"},{"id":"A165","pred":"fma_id","subj":"T165","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A166","pred":"fma_id","subj":"T166","obj":"http://purl.org/sig/ont/fma/fma62879"},{"id":"A167","pred":"fma_id","subj":"T167","obj":"http://purl.org/sig/ont/fma/fma67095"},{"id":"A168","pred":"fma_id","subj":"T168","obj":"http://purl.org/sig/ont/fma/fma62925"},{"id":"A169","pred":"fma_id","subj":"T169","obj":"http://purl.org/sig/ont/fma/fma82740"},{"id":"A170","pred":"fma_id","subj":"T170","obj":"http://purl.org/sig/ont/fma/fma82757"},{"id":"A171","pred":"fma_id","subj":"T171","obj":"http://purl.org/sig/ont/fma/fma67257"},{"id":"A172","pred":"fma_id","subj":"T172","obj":"http://purl.org/sig/ont/fma/fma67257"},{"id":"A173","pred":"fma_id","subj":"T173","obj":"http://purl.org/sig/ont/fma/fma62869"},{"id":"A174","pred":"fma_id","subj":"T174","obj":"http://purl.org/sig/ont/fma/fma70573"},{"id":"A175","pred":"fma_id","subj":"T175","obj":"http://purl.org/sig/ont/fma/fma62870"},{"id":"A176","pred":"fma_id","subj":"T176","obj":"http://purl.org/sig/ont/fma/fma62871"},{"id":"A177","pred":"fma_id","subj":"T177","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A178","pred":"fma_id","subj":"T178","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A179","pred":"fma_id","subj":"T179","obj":"http://purl.org/sig/ont/fma/fma84079"},{"id":"A180","pred":"fma_id","subj":"T180","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A181","pred":"fma_id","subj":"T181","obj":"http://purl.org/sig/ont/fma/fma63147"},{"id":"A182","pred":"fma_id","subj":"T182","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A183","pred":"fma_id","subj":"T183","obj":"http://purl.org/sig/ont/fma/fma70572"},{"id":"A184","pred":"fma_id","subj":"T184","obj":"http://purl.org/sig/ont/fma/fma62870"},{"id":"A185","pred":"fma_id","subj":"T185","obj":"http://purl.org/sig/ont/fma/fma84050"},{"id":"A186","pred":"fma_id","subj":"T186","obj":"http://purl.org/sig/ont/fma/fma84050"},{"id":"A187","pred":"fma_id","subj":"T187","obj":"http://purl.org/sig/ont/fma/fma84050"},{"id":"A188","pred":"fma_id","subj":"T188","obj":"http://purl.org/sig/ont/fma/fma84050"},{"id":"A189","pred":"fma_id","subj":"T189","obj":"http://purl.org/sig/ont/fma/fma86583"},{"id":"A190","pred":"fma_id","subj":"T190","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A191","pred":"fma_id","subj":"T191","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A192","pred":"fma_id","subj":"T192","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A193","pred":"fma_id","subj":"T193","obj":"http://purl.org/sig/ont/fma/fma9825"},{"id":"A194","pred":"fma_id","subj":"T194","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A195","pred":"fma_id","subj":"T195","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A196","pred":"fma_id","subj":"T196","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A197","pred":"fma_id","subj":"T197","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A198","pred":"fma_id","subj":"T198","obj":"http://purl.org/sig/ont/fma/fma67095"},{"id":"A199","pred":"fma_id","subj":"T199","obj":"http://purl.org/sig/ont/fma/fma67257"},{"id":"A200","pred":"fma_id","subj":"T200","obj":"http://purl.org/sig/ont/fma/fma67257"},{"id":"A201","pred":"fma_id","subj":"T201","obj":"http://purl.org/sig/ont/fma/fma66772"},{"id":"A202","pred":"fma_id","subj":"T202","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A203","pred":"fma_id","subj":"T203","obj":"http://purl.org/sig/ont/fma/fma69050"},{"id":"A204","pred":"fma_id","subj":"T204","obj":"http://purl.org/sig/ont/fma/fma9639"},{"id":"A205","pred":"fma_id","subj":"T205","obj":"http://purl.org/sig/ont/fma/fma68877"},{"id":"A206","pred":"fma_id","subj":"T206","obj":"http://purl.org/sig/ont/fma/fma7199"},{"id":"A207","pred":"fma_id","subj":"T207","obj":"http://purl.org/sig/ont/fma/fma7088"},{"id":"A208","pred":"fma_id","subj":"T208","obj":"http://purl.org/sig/ont/fma/fma50801"},{"id":"A209","pred":"fma_id","subj":"T209","obj":"http://purl.org/sig/ont/fma/fma7203"},{"id":"A210","pred":"fma_id","subj":"T210","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A211","pred":"fma_id","subj":"T211","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A212","pred":"fma_id","subj":"T212","obj":"http://purl.org/sig/ont/fma/fma7199"},{"id":"A213","pred":"fma_id","subj":"T213","obj":"http://purl.org/sig/ont/fma/fma82739"},{"id":"A214","pred":"fma_id","subj":"T214","obj":"http://purl.org/sig/ont/fma/fma7199"},{"id":"A215","pred":"fma_id","subj":"T215","obj":"http://purl.org/sig/ont/fma/fma67257"},{"id":"A216","pred":"fma_id","subj":"T216","obj":"http://purl.org/sig/ont/fma/fma9825"},{"id":"A217","pred":"fma_id","subj":"T217","obj":"http://purl.org/sig/ont/fma/fma9637"},{"id":"A218","pred":"fma_id","subj":"T218","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A219","pred":"fma_id","subj":"T219","obj":"http://purl.org/sig/ont/fma/fma66772"},{"id":"A220","pred":"fma_id","subj":"T220","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A221","pred":"fma_id","subj":"T221","obj":"http://purl.org/sig/ont/fma/fma84050"},{"id":"A222","pred":"fma_id","subj":"T222","obj":"http://purl.org/sig/ont/fma/fma67257"},{"id":"A223","pred":"fma_id","subj":"T223","obj":"http://purl.org/sig/ont/fma/fma82764"},{"id":"A224","pred":"fma_id","subj":"T224","obj":"http://purl.org/sig/ont/fma/fma9670"},{"id":"A225","pred":"fma_id","subj":"T225","obj":"http://purl.org/sig/ont/fma/fma12520"},{"id":"A226","pred":"fma_id","subj":"T226","obj":"http://purl.org/sig/ont/fma/fma62860"},{"id":"A227","pred":"fma_id","subj":"T227","obj":"http://purl.org/sig/ont/fma/fma67243"},{"id":"A228","pred":"fma_id","subj":"T228","obj":"http://purl.org/sig/ont/fma/fma84050"},{"id":"A229","pred":"fma_id","subj":"T229","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A230","pred":"fma_id","subj":"T230","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A231","pred":"fma_id","subj":"T231","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A232","pred":"fma_id","subj":"T232","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A233","pred":"fma_id","subj":"T233","obj":"http://purl.org/sig/ont/fma/fma84050"},{"id":"A234","pred":"fma_id","subj":"T234","obj":"http://purl.org/sig/ont/fma/fma86583"},{"id":"A235","pred":"fma_id","subj":"T235","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A236","pred":"fma_id","subj":"T236","obj":"http://purl.org/sig/ont/fma/fma68877"},{"id":"A237","pred":"fma_id","subj":"T237","obj":"http://purl.org/sig/ont/fma/fma62499"},{"id":"A238","pred":"fma_id","subj":"T238","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A239","pred":"fma_id","subj":"T239","obj":"http://purl.org/sig/ont/fma/fma63877"},{"id":"A240","pred":"fma_id","subj":"T240","obj":"http://purl.org/sig/ont/fma/fma84050"},{"id":"A241","pred":"fma_id","subj":"T241","obj":"http://purl.org/sig/ont/fma/fma9639"},{"id":"A242","pred":"fma_id","subj":"T242","obj":"http://purl.org/sig/ont/fma/fma86583"},{"id":"A243","pred":"fma_id","subj":"T243","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A244","pred":"fma_id","subj":"T244","obj":"http://purl.org/sig/ont/fma/fma27360"},{"id":"A245","pred":"fma_id","subj":"T245","obj":"http://purl.org/sig/ont/fma/fma63261"},{"id":"A246","pred":"fma_id","subj":"T246","obj":"http://purl.org/sig/ont/fma/fma273565"},{"id":"A247","pred":"fma_id","subj":"T247","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A248","pred":"fma_id","subj":"T248","obj":"http://purl.org/sig/ont/fma/fma86583"},{"id":"A249","pred":"fma_id","subj":"T249","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A250","pred":"fma_id","subj":"T250","obj":"http://purl.org/sig/ont/fma/fma9637"},{"id":"A251","pred":"fma_id","subj":"T251","obj":"http://purl.org/sig/ont/fma/fma82740"},{"id":"A252","pred":"fma_id","subj":"T252","obj":"http://purl.org/sig/ont/fma/fma67257"},{"id":"A253","pred":"fma_id","subj":"T253","obj":"http://purl.org/sig/ont/fma/fma86583"},{"id":"A254","pred":"fma_id","subj":"T254","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A255","pred":"fma_id","subj":"T255","obj":"http://purl.org/sig/ont/fma/fma86583"},{"id":"A256","pred":"fma_id","subj":"T256","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A257","pred":"fma_id","subj":"T257","obj":"http://purl.org/sig/ont/fma/fma86583"},{"id":"A258","pred":"fma_id","subj":"T258","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A259","pred":"fma_id","subj":"T259","obj":"http://purl.org/sig/ont/fma/fma86578"},{"id":"A260","pred":"fma_id","subj":"T260","obj":"http://purl.org/sig/ont/fma/fma74315"},{"id":"A261","pred":"fma_id","subj":"T261","obj":"http://purl.org/sig/ont/fma/fma20110"},{"id":"A262","pred":"fma_id","subj":"T262","obj":"http://purl.org/sig/ont/fma/fma9825"},{"id":"A263","pred":"fma_id","subj":"T263","obj":"http://purl.org/sig/ont/fma/fma82763"},{"id":"A264","pred":"fma_id","subj":"T264","obj":"http://purl.org/sig/ont/fma/fma82752"},{"id":"A265","pred":"fma_id","subj":"T265","obj":"http://purl.org/sig/ont/fma/fma82738"}],"text":"Immune system, inflammation and COVID-19\nThe immune system protects the human body from infections by a series of pathogen (bacteria, viruses, fungi, parasites) [5]. A self-tolerance system prevents the immune response from damaging human tissues. The immune system is always active, carrying out surveillance. The defense to first exposure to the pathogen is represented by two complementary and cooperating functional divisions, the innate immune and, on the other hand, the adaptive immune response, that represents a response based on previous exposure [6]. The innate immune system is represented by dendritic cells, macrophages and neutrophils, with phagocytic activity, and by eosinophils, mast cells and natural killer cells, which release specific soluble antimicrobial factors. The innate immune system includes physical barriers, represented by interconnected epithelial cells (e.g. tight junctions and cellular interactions mediated by cadherin), epithelial cilia and the mucus layer of the respiratory, gastrointestinal and genitourinary epithelium. Moreover, soluble proteins and small bioactive molecules such as complement proteins, defensins and ficolins 1-3, pro-inflammatory cytokines, chemokines, lipid mediators of inflammation, membrane-bound receptors and cytoplasmic proteins are part of the innate immune system. Both innate and adaptive immunity is mediated by leukocytes. Lymphocytes circulate between the blood system and the lymphatic system, passing through the peripheral lymphoid organs, which includes the spleen, tonsils, appendix, lymph nodes and gut-associated lymphoid tissue (GALT). From a common lymphoid progenitor, four major populations of mature lymphocytes are derived, that belong to the adaptive immune system: of B lymphocytes (B cells) and T lymphocytes (T cells), natural killer (NK) cells, and NK-T cells. T-cells can be further categorized to cytotoxic T-cells (TC cells), helper T-cells (Th) and suppressor T-cells. The specific antigenic receptors of the adaptive response are represented by genes that code for an intact T cell receptor (TCR) and immunoglobulin genes (B cell antigen receptor; Ig). TCR is capable of binding the antigen processed by antigen-presenting cells (APC). Dendritic cells represent the most powerful class of APC, and express molecules of the major histocompatibility complex (MHC) of class I and II, necessary for the recognition of the antigen processed by TCR on T cells [7].\nFollowing the presentation of viral antigens via MHC II, the T helper CD4+ lymphocytes are activated and switch to the T helper 1 phenotype [8].\nThe activated T helper lymphocytes proliferate and release cytokines: after stimulation by antigen and APC, the Th0 cells begin to produce interleukin (IL)-2. Meanwhile, Th cells differentiate into Th1, Th2 and Th17 according to the nature of the cytokines present in the activation site: IL-12 produced by macrophages and type I Interferon (IFN) or NK cells induce differentiation towards Th1, IL-4 produced by NK1.1 + T cells, basophils or mast cells induce differentiation towards Th2, and IL-1b, IL-23, TGFβ and IL-6 induce differentiation towards Th17 [9]. Th17 cells produce IL-17 and IL-22, and antigen-induced Treg (iTreg).\nThe binding of the cytokine to its transmembrane cell surface receptor activates an intracellular signal transduction pathway, generally a Janus kinase (Jak), which, via a kinase cascade, phosphorylates its transcription protein (STAT). Phosphorylated STAT dimers and moves to the nucleus, initiating a new gene transcription. Mutation of STAT1 increases susceptibility to virus infections because it is involved in various signalling pathways, including IFN-α/β, IFN- γ, IFN-l, IL-2, IL-3, IL-6, IL-9, IL-10, IL-11, IL-12, IL-15, IL-21, IL-22, IL-26 and IL-27 [10], and chemokines of several types such as C-X-C motif chemokine ligand 10 (CXCL-10), Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted (RANTES)/Chemokine (C–C motif) ligand 5 (CCL-5), Monocyte Chemoattractant Protein-1 (MCP-1) [11]. IFN-γ promotes antigen-specific antibody production, increasing the activity of phagocytosis. In the meantime, PRRs trigger inflammatory signalling, with activation of transcription factors like nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). NFκB is the key transcriptional regulator of many pro-inflammatory cytokines, adhesion molecules, chemokines, growth factors and other mediators of inflammation, as tumour necrosis factor (TNF), interleukins 1 (IL-1β), 6 (IL-6), and 12 (IL-12), promotes cellular proliferation and protects against apoptosis providing a mechanism that determines chronic inflammation. The recognition of pathogens is achieved through the presence of pattern recognition receptors (PRRs) [12]. PRRs identify the microbe-associated molecular patterns (MAMPs), and defensive responses is activated. PRRs include Toll-like receptors (TLRs), that are able to recognize viral DNA, viral double-stranded RNA and viral single-stranded RNA. TLRs are expressed on macrophages, dendritic cells, neutrophils, eosinophils, epithelial cells and keratinocytes. In particular, intracellular TLR-7 and TLR-8 allow the innate recognition of the single-stranded RNA of coronaviruses [13]. Intracellular and extracellular PRRs recognized spike glycoprotein, of the coronavirus coat, starting the inflammatory process, through the NFκB pathway [14]. Moreover, Nucleotide-Binding Domain, Leucine-Rich Repeat (NLR) proteins have also been identified, and NALP3 (NACHT, LRR and PYD domains-containing protein 3) has a special function in the innate immune response [15]. The processes involved in antiviral immunity is shown in Fig. 1.\nFig. 1 Graphical representation of antiviral SARS-Coronavirus 2 immunity. B: B lymphocyte; CTL: cytotoxic; T lymphocyte; IFN: interferon; Ig: immunoglobulin; IL: interleukin; MHC: major histocompatibility class; NFκB: nuclear factor kappa-light- chain- enhancer of activated B cells; NK: natural killer cell; Th: helper T lymphocyte; TLR: Toll-like receptor; TNF: tumour necrosis factor\nNormal inflammation is self-limiting because the production of pro-inflammatory cytokines (Th1 cytokines) is followed almost immediately by the production of anti-inflammatory cytokines (Th2 cytokines; IL-1, IL-10, IL-13, etc.). Chronic inflammation seems to result when the initiating factors persist, or there is some sort of failure of the resolution process.\nDysfunction of the immune system and the loss of homeostatic equilibrium between TREG cells (IL- 10) and Th17 cells (IL-17) was observed in different pathological situations [16], and it is believed to increase the risk of viral infections, including SARS- coronavirus 2 (SARS-CoV-2) [14].\nSARS-CoV-2 is an enveloped positive-strand RNA virus in the family Coronaviridae, group 2b, which encodes the viral replicase and four structural proteins: spike (S), envelope (E) and membrane (M), present in the viral envelope, and nucleocapsid (N) [17].\nThe access route of SARS-CoV-2 is represented by a hydrophobic pocket of the extracellular catalytic domain of Angiotensin-converting enzyme 2 (ACE2) [18]. SARS-CoV peak S protein trimers bind ACE2, expressed in endothelial cells of the vasculature and in the epithelia of the lungs, intestine, heart, brain and kidney. SARS-CoV-2 enters the cell for endocytosis and membrane fusion. Once the virus has infected the cell, it follows a downregulation of ACE2 with a consequent local increase in the levels of Ang II, and the development of acute respiratory distress syndrome (ARDS) [19]. The role of ACE2 in the gut, for expression of neutral amino acid transporters, could explain diarrhoea and intestinal inflammation observed in COVID-19. Moreover, SARS-CoV2 protein E activates the NFκB inflammatory pathway with the consequent activation of MAPK p38, resulting in exacerbation of inflammation and immunopathology [20]. Following the SARS-CoV-2 infection, in the incubation stage and in the non-serious form of COVID-19, the immune system activates the specific adaptive immune response to eliminate the virus, which should be sufficient to block viral propagation and disease progression. The antiviral system functions well in the presence of general good health and an adequate genetic background. However, the presence of concomitant pathologies (obesity, cardiovascular diseases, diabetes, neurodegenerative diseases and cancer), malnutrition, and impaired immune response determine the spread of the virus and a massive destruction of the affected tissues, especially in organs that have high ACE2 expression [21]. As noted earlier, SARS-CoV-2 enters the cell via ACE2; that inactivates des-Arg bradykinin, which is a potent ligand of the bradykinin receptor type 1 (BDKRB1).This receptor, localized on endothelial cells, is up-regulated by inflammatory cytokines, which is unlike the B2 receptor, that is constituently expressed and is the receptor for bradykinin (BDK). BDK is produced from an inactive pre-protein kininogen through activation by the serine protease kallikrein; in addition, it is considered a potent regulator of blood pressure [22], because it induces vasodilation, natriuresis, and hypotension upon activation of the BDKRB2 receptor. BDK is strongly integrated with the RAS, and the BDK receptor signaling is increased by angiotensin’s action [23].\nInterestingly, ACE has a higher affinity for BDK [24] and therefore in conditions where ACE is low, the vasopressor system is moved toward a BDK-directed hypotensive axis. BDK takes part in the inflammatory response after injury and acts to induce pain via stimulation of the BDKRB1 receptor, which also causes neutrophil recruitment and a major vascular permeability [25, 26].\nDuring the infection, as long as the virus persists, there is dysfunction of ACE2 function, leading to the dysregulation of the kinin-kallikrein pathway and thus causing the angioedema [27]. Some evidence that the edema is bradykinin-generated includes resistance to corticosteroids, epinephrine, and antihistamines in the management of reducing the pulmonary edema in COVID-19 patients. In fact, the so called Bradykinin Storm is likely responsible for most of the observed COVID-19 symptoms.\nInflammation plays a fundamental role in the pathogenesis and progression of COVID-19, ranging from common colds to fatal cases of pneumonia due to the cytokine release syndrome (CRS) that affected patients, determining the severe conditions. In COVID-19 the homeostatic equilibrium between TREG cells (IL-10) and Th17 cells (IL-17) is broken: inflammatory cytokine levels (IL-1, TNF) are elevated in the lungs of COVID-19 patients, resulting in an increase in HA-synthase-2 (HAS2) in alveolar epithelial cells CD31+, EpCAM+ and fibroblasts. The imbalance between pro-inflammatory and anti-inflammatory cytokines, leads to the CRS, an excessive and damaging host inflammation [28]. As a consequence of CRS [29], due to a severe infection of SARS-CoV-2 of the respiratory epithelium, the ARDS was observed in COVID-19 [30]. Edema and an IL-1β mediated proinflammatory response were increased in the lung parenchyma. Macrophages and dendritic cells produce IL-1β through macro-molecular complexes called inflammasomes, including the major element present in the pulmonary tissue and the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome [20]. Following a precise stimulus, the activation and recruitment domain of caspase (ASC) and the catalytically inactive procaspase-1 assemble, the procaspase-1 turns into active caspase-1, the inactive pro-IL-1β matures in IL-1β and the NLRP3 inflammasome is activated. The NLRP3 inflammasomes and IL-1β driven proinflammatory cascades correlate with worsening of several respiratory diseases, including COVID-19.\nPatients affected by obesity showed a severe consequence of COVID-19 [31], due to the high concentrations of TNF-α, MCP-1 and IL-6 produced in the meantime by visceral and subcutaneous adipose tissue and by innate immunity [32]. Moreover, leptin, released by adipose tissue, helps to increase inflammatory milieu with a dysregulation of the immune response [33].\nThis umbrella review seeks to answer the question of whether a nutritional approach can be used to enhance the immune system’s response to obesity in obese patients affected by COVID-19.\nImmunonutrition has been based on the concept that malnutrition impairs immune function, used to modify inflammatory or immune responses. This concept may be applied to any situation in which a supply of specific nutrients is necessary to modify inflammatory or immune responses. Immunonutrients can promote patient recovery by inhibiting inflammatory responses and regulating immune function. Therefore, immunonutrition involves feeding enriched with various pharmaconutrients (arginine, glutamine, omega-3-fatty acids, ribonucleotides and certain trace elements and antioxidants compound, vitamins and minerals) to modulate inflammatory responses, the acquired immune response, and to improve patient outcomes [34].\nPersonalized immunonutrition for patients with obesity should be the first therapeutic choice to reduce the risk of infections and the disease course in COVID-19 patients. That therapeutic strategy could be effective in case of other potential epidemic infections. It would also allow a reduction of the enormous medical care cost supported by the National Health Service."}

{"project":"LitCovid-PD-UBERON","denotations":[{"id":"T16","span":{"begin":0,"end":13},"obj":"Body_part"},{"id":"T17","span":{"begin":45,"end":58},"obj":"Body_part"},{"id":"T18","span":{"begin":252,"end":265},"obj":"Body_part"},{"id":"T19","span":{"begin":467,"end":471},"obj":"Body_part"},{"id":"T20","span":{"begin":573,"end":586},"obj":"Body_part"},{"id":"T21","span":{"begin":799,"end":812},"obj":"Body_part"},{"id":"T22","span":{"begin":984,"end":989},"obj":"Body_part"},{"id":"T23","span":{"begin":1051,"end":1061},"obj":"Body_part"},{"id":"T24","span":{"begin":1323,"end":1336},"obj":"Body_part"},{"id":"T25","span":{"begin":1433,"end":1438},"obj":"Body_part"},{"id":"T26","span":{"begin":1512,"end":1518},"obj":"Body_part"},{"id":"T27","span":{"begin":1539,"end":1545},"obj":"Body_part"},{"id":"T28","span":{"begin":1566,"end":1577},"obj":"Body_part"},{"id":"T29","span":{"begin":1566,"end":1571},"obj":"Body_part"},{"id":"T30","span":{"begin":1582,"end":1612},"obj":"Body_part"},{"id":"T31","span":{"begin":1597,"end":1612},"obj":"Body_part"},{"id":"T32","span":{"begin":1606,"end":1612},"obj":"Body_part"},{"id":"T33","span":{"begin":1742,"end":1755},"obj":"Body_part"},{"id":"T34","span":{"begin":6489,"end":6502},"obj":"Body_part"},{"id":"T35","span":{"begin":7253,"end":7264},"obj":"Body_part"},{"id":"T36","span":{"begin":7276,"end":7285},"obj":"Body_part"},{"id":"T37","span":{"begin":7300,"end":7309},"obj":"Body_part"},{"id":"T38","span":{"begin":7311,"end":7316},"obj":"Body_part"},{"id":"T39","span":{"begin":7318,"end":7323},"obj":"Body_part"},{"id":"T40","span":{"begin":7328,"end":7334},"obj":"Body_part"},{"id":"T41","span":{"begin":8045,"end":8058},"obj":"Body_part"},{"id":"T42","span":{"begin":8597,"end":8603},"obj":"Body_part"},{"id":"T43","span":{"begin":9159,"end":9164},"obj":"Body_part"},{"id":"T44","span":{"begin":11040,"end":11050},"obj":"Body_part"},{"id":"T45","span":{"begin":11167,"end":11182},"obj":"Body_part"},{"id":"T46","span":{"begin":11167,"end":11171},"obj":"Body_part"},{"id":"T47","span":{"begin":11172,"end":11182},"obj":"Body_part"},{"id":"T48","span":{"begin":11339,"end":11345},"obj":"Body_part"},{"id":"T49","span":{"begin":12059,"end":12086},"obj":"Body_part"},{"id":"T50","span":{"begin":12072,"end":12086},"obj":"Body_part"},{"id":"T51","span":{"begin":12080,"end":12086},"obj":"Body_part"},{"id":"T52","span":{"begin":12146,"end":12160},"obj":"Body_part"},{"id":"T53","span":{"begin":12154,"end":12160},"obj":"Body_part"},{"id":"T54","span":{"begin":12361,"end":12376},"obj":"Body_part"}],"attributes":[{"id":"A16","pred":"uberon_id","subj":"T16","obj":"http://purl.obolibrary.org/obo/UBERON_0002405"},{"id":"A17","pred":"uberon_id","subj":"T17","obj":"http://purl.obolibrary.org/obo/UBERON_0002405"},{"id":"A18","pred":"uberon_id","subj":"T18","obj":"http://purl.obolibrary.org/obo/UBERON_0002405"},{"id":"A19","pred":"uberon_id","subj":"T19","obj":"http://purl.obolibrary.org/obo/UBERON_0002398"},{"id":"A20","pred":"uberon_id","subj":"T20","obj":"http://purl.obolibrary.org/obo/UBERON_0002405"},{"id":"A21","pred":"uberon_id","subj":"T21","obj":"http://purl.obolibrary.org/obo/UBERON_0002405"},{"id":"A22","pred":"uberon_id","subj":"T22","obj":"http://purl.obolibrary.org/obo/UBERON_0000912"},{"id":"A23","pred":"uberon_id","subj":"T23","obj":"http://purl.obolibrary.org/obo/UBERON_0000483"},{"id":"A24","pred":"uberon_id","subj":"T24","obj":"http://purl.obolibrary.org/obo/UBERON_0002405"},{"id":"A25","pred":"uberon_id","subj":"T25","obj":"http://purl.obolibrary.org/obo/UBERON_0000178"},{"id":"A26","pred":"uberon_id","subj":"T26","obj":"http://purl.obolibrary.org/obo/UBERON_0000062"},{"id":"A27","pred":"uberon_id","subj":"T27","obj":"http://purl.obolibrary.org/obo/UBERON_0002106"},{"id":"A28","pred":"uberon_id","subj":"T28","obj":"http://purl.obolibrary.org/obo/UBERON_0000029"},{"id":"A29","pred":"uberon_id","subj":"T29","obj":"http://purl.obolibrary.org/obo/UBERON_0002391"},{"id":"A30","pred":"uberon_id","subj":"T30","obj":"http://purl.obolibrary.org/obo/UBERON_0001962"},{"id":"A31","pred":"uberon_id","subj":"T31","obj":"http://purl.obolibrary.org/obo/UBERON_0001744"},{"id":"A32","pred":"uberon_id","subj":"T32","obj":"http://purl.obolibrary.org/obo/UBERON_0000479"},{"id":"A33","pred":"uberon_id","subj":"T33","obj":"http://purl.obolibrary.org/obo/UBERON_0002405"},{"id":"A34","pred":"uberon_id","subj":"T34","obj":"http://purl.obolibrary.org/obo/UBERON_0002405"},{"id":"A35","pred":"uberon_id","subj":"T35","obj":"http://purl.obolibrary.org/obo/UBERON_0002049"},{"id":"A36","pred":"uberon_id","subj":"T36","obj":"http://purl.obolibrary.org/obo/UBERON_0000483"},{"id":"A37","pred":"uberon_id","subj":"T37","obj":"http://purl.obolibrary.org/obo/UBERON_0000160"},{"id":"A38","pred":"uberon_id","subj":"T38","obj":"http://purl.obolibrary.org/obo/UBERON_0000948"},{"id":"A39","pred":"uberon_id","subj":"T39","obj":"http://purl.obolibrary.org/obo/UBERON_0000955"},{"id":"A40","pred":"uberon_id","subj":"T40","obj":"http://purl.obolibrary.org/obo/UBERON_0002113"},{"id":"A41","pred":"uberon_id","subj":"T41","obj":"http://purl.obolibrary.org/obo/UBERON_0002405"},{"id":"A42","pred":"uberon_id","subj":"T42","obj":"http://purl.obolibrary.org/obo/UBERON_0000062"},{"id":"A43","pred":"uberon_id","subj":"T43","obj":"http://purl.obolibrary.org/obo/UBERON_0000178"},{"id":"A44","pred":"uberon_id","subj":"T44","obj":"http://purl.obolibrary.org/obo/UBERON_0000483"},{"id":"A45","pred":"uberon_id","subj":"T45","obj":"http://purl.obolibrary.org/obo/UBERON_0008946"},{"id":"A46","pred":"uberon_id","subj":"T46","obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"A47","pred":"uberon_id","subj":"T47","obj":"http://purl.obolibrary.org/obo/UBERON_0000353"},{"id":"A48","pred":"uberon_id","subj":"T48","obj":"http://purl.obolibrary.org/obo/UBERON_0000479"},{"id":"A49","pred":"uberon_id","subj":"T49","obj":"http://purl.obolibrary.org/obo/UBERON_0002190"},{"id":"A50","pred":"uberon_id","subj":"T50","obj":"http://purl.obolibrary.org/obo/UBERON_0001013"},{"id":"A51","pred":"uberon_id","subj":"T51","obj":"http://purl.obolibrary.org/obo/UBERON_0000479"},{"id":"A52","pred":"uberon_id","subj":"T52","obj":"http://purl.obolibrary.org/obo/UBERON_0001013"},{"id":"A53","pred":"uberon_id","subj":"T53","obj":"http://purl.obolibrary.org/obo/UBERON_0000479"},{"id":"A54","pred":"uberon_id","subj":"T54","obj":"http://purl.obolibrary.org/obo/UBERON_0002405"}],"text":"Immune system, inflammation and COVID-19\nThe immune system protects the human body from infections by a series of pathogen (bacteria, viruses, fungi, parasites) [5]. A self-tolerance system prevents the immune response from damaging human tissues. The immune system is always active, carrying out surveillance. The defense to first exposure to the pathogen is represented by two complementary and cooperating functional divisions, the innate immune and, on the other hand, the adaptive immune response, that represents a response based on previous exposure [6]. The innate immune system is represented by dendritic cells, macrophages and neutrophils, with phagocytic activity, and by eosinophils, mast cells and natural killer cells, which release specific soluble antimicrobial factors. The innate immune system includes physical barriers, represented by interconnected epithelial cells (e.g. tight junctions and cellular interactions mediated by cadherin), epithelial cilia and the mucus layer of the respiratory, gastrointestinal and genitourinary epithelium. Moreover, soluble proteins and small bioactive molecules such as complement proteins, defensins and ficolins 1-3, pro-inflammatory cytokines, chemokines, lipid mediators of inflammation, membrane-bound receptors and cytoplasmic proteins are part of the innate immune system. Both innate and adaptive immunity is mediated by leukocytes. Lymphocytes circulate between the blood system and the lymphatic system, passing through the peripheral lymphoid organs, which includes the spleen, tonsils, appendix, lymph nodes and gut-associated lymphoid tissue (GALT). From a common lymphoid progenitor, four major populations of mature lymphocytes are derived, that belong to the adaptive immune system: of B lymphocytes (B cells) and T lymphocytes (T cells), natural killer (NK) cells, and NK-T cells. T-cells can be further categorized to cytotoxic T-cells (TC cells), helper T-cells (Th) and suppressor T-cells. The specific antigenic receptors of the adaptive response are represented by genes that code for an intact T cell receptor (TCR) and immunoglobulin genes (B cell antigen receptor; Ig). TCR is capable of binding the antigen processed by antigen-presenting cells (APC). Dendritic cells represent the most powerful class of APC, and express molecules of the major histocompatibility complex (MHC) of class I and II, necessary for the recognition of the antigen processed by TCR on T cells [7].\nFollowing the presentation of viral antigens via MHC II, the T helper CD4+ lymphocytes are activated and switch to the T helper 1 phenotype [8].\nThe activated T helper lymphocytes proliferate and release cytokines: after stimulation by antigen and APC, the Th0 cells begin to produce interleukin (IL)-2. Meanwhile, Th cells differentiate into Th1, Th2 and Th17 according to the nature of the cytokines present in the activation site: IL-12 produced by macrophages and type I Interferon (IFN) or NK cells induce differentiation towards Th1, IL-4 produced by NK1.1 + T cells, basophils or mast cells induce differentiation towards Th2, and IL-1b, IL-23, TGFβ and IL-6 induce differentiation towards Th17 [9]. Th17 cells produce IL-17 and IL-22, and antigen-induced Treg (iTreg).\nThe binding of the cytokine to its transmembrane cell surface receptor activates an intracellular signal transduction pathway, generally a Janus kinase (Jak), which, via a kinase cascade, phosphorylates its transcription protein (STAT). Phosphorylated STAT dimers and moves to the nucleus, initiating a new gene transcription. Mutation of STAT1 increases susceptibility to virus infections because it is involved in various signalling pathways, including IFN-α/β, IFN- γ, IFN-l, IL-2, IL-3, IL-6, IL-9, IL-10, IL-11, IL-12, IL-15, IL-21, IL-22, IL-26 and IL-27 [10], and chemokines of several types such as C-X-C motif chemokine ligand 10 (CXCL-10), Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted (RANTES)/Chemokine (C–C motif) ligand 5 (CCL-5), Monocyte Chemoattractant Protein-1 (MCP-1) [11]. IFN-γ promotes antigen-specific antibody production, increasing the activity of phagocytosis. In the meantime, PRRs trigger inflammatory signalling, with activation of transcription factors like nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). NFκB is the key transcriptional regulator of many pro-inflammatory cytokines, adhesion molecules, chemokines, growth factors and other mediators of inflammation, as tumour necrosis factor (TNF), interleukins 1 (IL-1β), 6 (IL-6), and 12 (IL-12), promotes cellular proliferation and protects against apoptosis providing a mechanism that determines chronic inflammation. The recognition of pathogens is achieved through the presence of pattern recognition receptors (PRRs) [12]. PRRs identify the microbe-associated molecular patterns (MAMPs), and defensive responses is activated. PRRs include Toll-like receptors (TLRs), that are able to recognize viral DNA, viral double-stranded RNA and viral single-stranded RNA. TLRs are expressed on macrophages, dendritic cells, neutrophils, eosinophils, epithelial cells and keratinocytes. In particular, intracellular TLR-7 and TLR-8 allow the innate recognition of the single-stranded RNA of coronaviruses [13]. Intracellular and extracellular PRRs recognized spike glycoprotein, of the coronavirus coat, starting the inflammatory process, through the NFκB pathway [14]. Moreover, Nucleotide-Binding Domain, Leucine-Rich Repeat (NLR) proteins have also been identified, and NALP3 (NACHT, LRR and PYD domains-containing protein 3) has a special function in the innate immune response [15]. The processes involved in antiviral immunity is shown in Fig. 1.\nFig. 1 Graphical representation of antiviral SARS-Coronavirus 2 immunity. B: B lymphocyte; CTL: cytotoxic; T lymphocyte; IFN: interferon; Ig: immunoglobulin; IL: interleukin; MHC: major histocompatibility class; NFκB: nuclear factor kappa-light- chain- enhancer of activated B cells; NK: natural killer cell; Th: helper T lymphocyte; TLR: Toll-like receptor; TNF: tumour necrosis factor\nNormal inflammation is self-limiting because the production of pro-inflammatory cytokines (Th1 cytokines) is followed almost immediately by the production of anti-inflammatory cytokines (Th2 cytokines; IL-1, IL-10, IL-13, etc.). Chronic inflammation seems to result when the initiating factors persist, or there is some sort of failure of the resolution process.\nDysfunction of the immune system and the loss of homeostatic equilibrium between TREG cells (IL- 10) and Th17 cells (IL-17) was observed in different pathological situations [16], and it is believed to increase the risk of viral infections, including SARS- coronavirus 2 (SARS-CoV-2) [14].\nSARS-CoV-2 is an enveloped positive-strand RNA virus in the family Coronaviridae, group 2b, which encodes the viral replicase and four structural proteins: spike (S), envelope (E) and membrane (M), present in the viral envelope, and nucleocapsid (N) [17].\nThe access route of SARS-CoV-2 is represented by a hydrophobic pocket of the extracellular catalytic domain of Angiotensin-converting enzyme 2 (ACE2) [18]. SARS-CoV peak S protein trimers bind ACE2, expressed in endothelial cells of the vasculature and in the epithelia of the lungs, intestine, heart, brain and kidney. SARS-CoV-2 enters the cell for endocytosis and membrane fusion. Once the virus has infected the cell, it follows a downregulation of ACE2 with a consequent local increase in the levels of Ang II, and the development of acute respiratory distress syndrome (ARDS) [19]. The role of ACE2 in the gut, for expression of neutral amino acid transporters, could explain diarrhoea and intestinal inflammation observed in COVID-19. Moreover, SARS-CoV2 protein E activates the NFκB inflammatory pathway with the consequent activation of MAPK p38, resulting in exacerbation of inflammation and immunopathology [20]. Following the SARS-CoV-2 infection, in the incubation stage and in the non-serious form of COVID-19, the immune system activates the specific adaptive immune response to eliminate the virus, which should be sufficient to block viral propagation and disease progression. The antiviral system functions well in the presence of general good health and an adequate genetic background. However, the presence of concomitant pathologies (obesity, cardiovascular diseases, diabetes, neurodegenerative diseases and cancer), malnutrition, and impaired immune response determine the spread of the virus and a massive destruction of the affected tissues, especially in organs that have high ACE2 expression [21]. As noted earlier, SARS-CoV-2 enters the cell via ACE2; that inactivates des-Arg bradykinin, which is a potent ligand of the bradykinin receptor type 1 (BDKRB1).This receptor, localized on endothelial cells, is up-regulated by inflammatory cytokines, which is unlike the B2 receptor, that is constituently expressed and is the receptor for bradykinin (BDK). BDK is produced from an inactive pre-protein kininogen through activation by the serine protease kallikrein; in addition, it is considered a potent regulator of blood pressure [22], because it induces vasodilation, natriuresis, and hypotension upon activation of the BDKRB2 receptor. BDK is strongly integrated with the RAS, and the BDK receptor signaling is increased by angiotensin’s action [23].\nInterestingly, ACE has a higher affinity for BDK [24] and therefore in conditions where ACE is low, the vasopressor system is moved toward a BDK-directed hypotensive axis. BDK takes part in the inflammatory response after injury and acts to induce pain via stimulation of the BDKRB1 receptor, which also causes neutrophil recruitment and a major vascular permeability [25, 26].\nDuring the infection, as long as the virus persists, there is dysfunction of ACE2 function, leading to the dysregulation of the kinin-kallikrein pathway and thus causing the angioedema [27]. Some evidence that the edema is bradykinin-generated includes resistance to corticosteroids, epinephrine, and antihistamines in the management of reducing the pulmonary edema in COVID-19 patients. In fact, the so called Bradykinin Storm is likely responsible for most of the observed COVID-19 symptoms.\nInflammation plays a fundamental role in the pathogenesis and progression of COVID-19, ranging from common colds to fatal cases of pneumonia due to the cytokine release syndrome (CRS) that affected patients, determining the severe conditions. In COVID-19 the homeostatic equilibrium between TREG cells (IL-10) and Th17 cells (IL-17) is broken: inflammatory cytokine levels (IL-1, TNF) are elevated in the lungs of COVID-19 patients, resulting in an increase in HA-synthase-2 (HAS2) in alveolar epithelial cells CD31+, EpCAM+ and fibroblasts. The imbalance between pro-inflammatory and anti-inflammatory cytokines, leads to the CRS, an excessive and damaging host inflammation [28]. As a consequence of CRS [29], due to a severe infection of SARS-CoV-2 of the respiratory epithelium, the ARDS was observed in COVID-19 [30]. Edema and an IL-1β mediated proinflammatory response were increased in the lung parenchyma. Macrophages and dendritic cells produce IL-1β through macro-molecular complexes called inflammasomes, including the major element present in the pulmonary tissue and the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome [20]. Following a precise stimulus, the activation and recruitment domain of caspase (ASC) and the catalytically inactive procaspase-1 assemble, the procaspase-1 turns into active caspase-1, the inactive pro-IL-1β matures in IL-1β and the NLRP3 inflammasome is activated. The NLRP3 inflammasomes and IL-1β driven proinflammatory cascades correlate with worsening of several respiratory diseases, including COVID-19.\nPatients affected by obesity showed a severe consequence of COVID-19 [31], due to the high concentrations of TNF-α, MCP-1 and IL-6 produced in the meantime by visceral and subcutaneous adipose tissue and by innate immunity [32]. Moreover, leptin, released by adipose tissue, helps to increase inflammatory milieu with a dysregulation of the immune response [33].\nThis umbrella review seeks to answer the question of whether a nutritional approach can be used to enhance the immune system’s response to obesity in obese patients affected by COVID-19.\nImmunonutrition has been based on the concept that malnutrition impairs immune function, used to modify inflammatory or immune responses. This concept may be applied to any situation in which a supply of specific nutrients is necessary to modify inflammatory or immune responses. Immunonutrients can promote patient recovery by inhibiting inflammatory responses and regulating immune function. Therefore, immunonutrition involves feeding enriched with various pharmaconutrients (arginine, glutamine, omega-3-fatty acids, ribonucleotides and certain trace elements and antioxidants compound, vitamins and minerals) to modulate inflammatory responses, the acquired immune response, and to improve patient outcomes [34].\nPersonalized immunonutrition for patients with obesity should be the first therapeutic choice to reduce the risk of infections and the disease course in COVID-19 patients. That therapeutic strategy could be effective in case of other potential epidemic infections. It would also allow a reduction of the enormous medical care cost supported by the National Health Service."}

{"project":"LitCovid-PD-MONDO","denotations":[{"id":"T33","span":{"begin":15,"end":27},"obj":"Disease"},{"id":"T34","span":{"begin":32,"end":40},"obj":"Disease"},{"id":"T35","span":{"begin":88,"end":98},"obj":"Disease"},{"id":"T36","span":{"begin":1236,"end":1248},"obj":"Disease"},{"id":"T37","span":{"begin":3609,"end":3625},"obj":"Disease"},{"id":"T38","span":{"begin":4473,"end":4485},"obj":"Disease"},{"id":"T39","span":{"begin":4679,"end":4691},"obj":"Disease"},{"id":"T40","span":{"begin":5765,"end":5769},"obj":"Disease"},{"id":"T41","span":{"begin":6114,"end":6126},"obj":"Disease"},{"id":"T42","span":{"begin":6344,"end":6356},"obj":"Disease"},{"id":"T43","span":{"begin":6693,"end":6709},"obj":"Disease"},{"id":"T44","span":{"begin":6721,"end":6725},"obj":"Disease"},{"id":"T45","span":{"begin":6742,"end":6750},"obj":"Disease"},{"id":"T46","span":{"begin":6760,"end":6768},"obj":"Disease"},{"id":"T47","span":{"begin":7036,"end":7044},"obj":"Disease"},{"id":"T48","span":{"begin":7172,"end":7180},"obj":"Disease"},{"id":"T49","span":{"begin":7336,"end":7344},"obj":"Disease"},{"id":"T50","span":{"begin":7555,"end":7590},"obj":"Disease"},{"id":"T51","span":{"begin":7561,"end":7590},"obj":"Disease"},{"id":"T52","span":{"begin":7592,"end":7596},"obj":"Disease"},{"id":"T53","span":{"begin":7698,"end":7707},"obj":"Disease"},{"id":"T54","span":{"begin":7712,"end":7735},"obj":"Disease"},{"id":"T55","span":{"begin":7723,"end":7735},"obj":"Disease"},{"id":"T56","span":{"begin":7748,"end":7756},"obj":"Disease"},{"id":"T57","span":{"begin":7768,"end":7772},"obj":"Disease"},{"id":"T58","span":{"begin":7901,"end":7913},"obj":"Disease"},{"id":"T59","span":{"begin":7954,"end":7962},"obj":"Disease"},{"id":"T60","span":{"begin":7965,"end":7974},"obj":"Disease"},{"id":"T61","span":{"begin":8031,"end":8039},"obj":"Disease"},{"id":"T62","span":{"begin":8371,"end":8378},"obj":"Disease"},{"id":"T63","span":{"begin":8380,"end":8403},"obj":"Disease"},{"id":"T64","span":{"begin":8405,"end":8413},"obj":"Disease"},{"id":"T65","span":{"begin":8415,"end":8441},"obj":"Disease"},{"id":"T66","span":{"begin":8446,"end":8452},"obj":"Disease"},{"id":"T67","span":{"begin":8455,"end":8467},"obj":"Disease"},{"id":"T68","span":{"begin":8659,"end":8667},"obj":"Disease"},{"id":"T69","span":{"begin":9230,"end":9241},"obj":"Disease"},{"id":"T70","span":{"begin":9619,"end":9625},"obj":"Disease"},{"id":"T71","span":{"begin":9786,"end":9795},"obj":"Disease"},{"id":"T72","span":{"begin":9949,"end":9959},"obj":"Disease"},{"id":"T73","span":{"begin":10125,"end":10140},"obj":"Disease"},{"id":"T74","span":{"begin":10144,"end":10152},"obj":"Disease"},{"id":"T75","span":{"begin":10250,"end":10258},"obj":"Disease"},{"id":"T76","span":{"begin":10269,"end":10281},"obj":"Disease"},{"id":"T77","span":{"begin":10346,"end":10354},"obj":"Disease"},{"id":"T78","span":{"begin":10369,"end":10381},"obj":"Disease"},{"id":"T79","span":{"begin":10400,"end":10409},"obj":"Disease"},{"id":"T80","span":{"begin":10448,"end":10451},"obj":"Disease"},{"id":"T82","span":{"begin":10515,"end":10523},"obj":"Disease"},{"id":"T83","span":{"begin":10683,"end":10691},"obj":"Disease"},{"id":"T84","span":{"begin":10896,"end":10899},"obj":"Disease"},{"id":"T86","span":{"begin":10932,"end":10944},"obj":"Disease"},{"id":"T87","span":{"begin":10971,"end":10974},"obj":"Disease"},{"id":"T89","span":{"begin":10997,"end":11006},"obj":"Disease"},{"id":"T90","span":{"begin":11010,"end":11018},"obj":"Disease"},{"id":"T91","span":{"begin":11056,"end":11060},"obj":"Disease"},{"id":"T92","span":{"begin":11077,"end":11085},"obj":"Disease"},{"id":"T93","span":{"begin":11397,"end":11400},"obj":"Disease"},{"id":"T94","span":{"begin":11557,"end":11560},"obj":"Disease"},{"id":"T95","span":{"begin":11845,"end":11865},"obj":"Disease"},{"id":"T96","span":{"begin":11877,"end":11885},"obj":"Disease"},{"id":"T97","span":{"begin":11908,"end":11915},"obj":"Disease"},{"id":"T98","span":{"begin":11947,"end":11955},"obj":"Disease"},{"id":"T99","span":{"begin":12059,"end":12086},"obj":"Disease"},{"id":"T100","span":{"begin":12389,"end":12396},"obj":"Disease"},{"id":"T101","span":{"begin":12427,"end":12435},"obj":"Disease"},{"id":"T102","span":{"begin":12488,"end":12500},"obj":"Disease"},{"id":"T103","span":{"begin":13202,"end":13209},"obj":"Disease"},{"id":"T104","span":{"begin":13271,"end":13281},"obj":"Disease"},{"id":"T105","span":{"begin":13308,"end":13316},"obj":"Disease"},{"id":"T106","span":{"begin":13408,"end":13418},"obj":"Disease"}],"attributes":[{"id":"A33","pred":"mondo_id","subj":"T33","obj":"http://purl.obolibrary.org/obo/MONDO_0021166"},{"id":"A34","pred":"mondo_id","subj":"T34","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A35","pred":"mondo_id","subj":"T35","obj":"http://purl.obolibrary.org/obo/MONDO_0005550"},{"id":"A36","pred":"mondo_id","subj":"T36","obj":"http://purl.obolibrary.org/obo/MONDO_0021166"},{"id":"A37","pred":"mondo_id","subj":"T37","obj":"http://purl.obolibrary.org/obo/MONDO_0005108"},{"id":"A38","pred":"mondo_id","subj":"T38","obj":"http://purl.obolibrary.org/obo/MONDO_0021166"},{"id":"A39","pred":"mondo_id","subj":"T39","obj":"http://purl.obolibrary.org/obo/MONDO_0021166"},{"id":"A40","pred":"mondo_id","subj":"T40","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A41","pred":"mondo_id","subj":"T41","obj":"http://purl.obolibrary.org/obo/MONDO_0021166"},{"id":"A42","pred":"mondo_id","subj":"T42","obj":"http://purl.obolibrary.org/obo/MONDO_0021166"},{"id":"A43","pred":"mondo_id","subj":"T43","obj":"http://purl.obolibrary.org/obo/MONDO_0005108"},{"id":"A44","pred":"mondo_id","subj":"T44","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A45","pred":"mondo_id","subj":"T45","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A46","pred":"mondo_id","subj":"T46","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A47","pred":"mondo_id","subj":"T47","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A48","pred":"mondo_id","subj":"T48","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A49","pred":"mondo_id","subj":"T49","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A50","pred":"mondo_id","subj":"T50","obj":"http://purl.obolibrary.org/obo/MONDO_0006502"},{"id":"A51","pred":"mondo_id","subj":"T51","obj":"http://purl.obolibrary.org/obo/MONDO_0009971"},{"id":"A52","pred":"mondo_id","subj":"T52","obj":"http://purl.obolibrary.org/obo/MONDO_0006502"},{"id":"A53","pred":"mondo_id","subj":"T53","obj":"http://purl.obolibrary.org/obo/MONDO_0001673"},{"id":"A54","pred":"mondo_id","subj":"T54","obj":"http://purl.obolibrary.org/obo/MONDO_0002269"},{"id":"A55","pred":"mondo_id","subj":"T55","obj":"http://purl.obolibrary.org/obo/MONDO_0021166"},{"id":"A56","pred":"mondo_id","subj":"T56","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A57","pred":"mondo_id","subj":"T57","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A58","pred":"mondo_id","subj":"T58","obj":"http://purl.obolibrary.org/obo/MONDO_0021166"},{"id":"A59","pred":"mondo_id","subj":"T59","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A60","pred":"mondo_id","subj":"T60","obj":"http://purl.obolibrary.org/obo/MONDO_0005550"},{"id":"A61","pred":"mondo_id","subj":"T61","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A62","pred":"mondo_id","subj":"T62","obj":"http://purl.obolibrary.org/obo/MONDO_0011122"},{"id":"A63","pred":"mondo_id","subj":"T63","obj":"http://purl.obolibrary.org/obo/MONDO_0004995"},{"id":"A64","pred":"mondo_id","subj":"T64","obj":"http://purl.obolibrary.org/obo/MONDO_0005015"},{"id":"A65","pred":"mondo_id","subj":"T65","obj":"http://purl.obolibrary.org/obo/MONDO_0005559"},{"id":"A66","pred":"mondo_id","subj":"T66","obj":"http://purl.obolibrary.org/obo/MONDO_0004992"},{"id":"A67","pred":"mondo_id","subj":"T67","obj":"http://purl.obolibrary.org/obo/MONDO_0006873"},{"id":"A68","pred":"mondo_id","subj":"T68","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A69","pred":"mondo_id","subj":"T69","obj":"http://purl.obolibrary.org/obo/MONDO_0005468"},{"id":"A70","pred":"mondo_id","subj":"T70","obj":"http://purl.obolibrary.org/obo/MONDO_0021178"},{"id":"A71","pred":"mondo_id","subj":"T71","obj":"http://purl.obolibrary.org/obo/MONDO_0005550"},{"id":"A72","pred":"mondo_id","subj":"T72","obj":"http://purl.obolibrary.org/obo/MONDO_0010481"},{"id":"A73","pred":"mondo_id","subj":"T73","obj":"http://purl.obolibrary.org/obo/MONDO_0006932"},{"id":"A74","pred":"mondo_id","subj":"T74","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A75","pred":"mondo_id","subj":"T75","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A76","pred":"mondo_id","subj":"T76","obj":"http://purl.obolibrary.org/obo/MONDO_0021166"},{"id":"A77","pred":"mondo_id","subj":"T77","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A78","pred":"mondo_id","subj":"T78","obj":"http://purl.obolibrary.org/obo/MONDO_0005709"},{"id":"A79","pred":"mondo_id","subj":"T79","obj":"http://purl.obolibrary.org/obo/MONDO_0005249"},{"id":"A80","pred":"mondo_id","subj":"T80","obj":"http://purl.obolibrary.org/obo/MONDO_0007399"},{"id":"A81","pred":"mondo_id","subj":"T80","obj":"http://purl.obolibrary.org/obo/MONDO_0017361"},{"id":"A82","pred":"mondo_id","subj":"T82","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A83","pred":"mondo_id","subj":"T83","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A84","pred":"mondo_id","subj":"T84","obj":"http://purl.obolibrary.org/obo/MONDO_0007399"},{"id":"A85","pred":"mondo_id","subj":"T84","obj":"http://purl.obolibrary.org/obo/MONDO_0017361"},{"id":"A86","pred":"mondo_id","subj":"T86","obj":"http://purl.obolibrary.org/obo/MONDO_0021166"},{"id":"A87","pred":"mondo_id","subj":"T87","obj":"http://purl.obolibrary.org/obo/MONDO_0007399"},{"id":"A88","pred":"mondo_id","subj":"T87","obj":"http://purl.obolibrary.org/obo/MONDO_0017361"},{"id":"A89","pred":"mondo_id","subj":"T89","obj":"http://purl.obolibrary.org/obo/MONDO_0005550"},{"id":"A90","pred":"mondo_id","subj":"T90","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A91","pred":"mondo_id","subj":"T91","obj":"http://purl.obolibrary.org/obo/MONDO_0006502"},{"id":"A92","pred":"mondo_id","subj":"T92","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A93","pred":"mondo_id","subj":"T93","obj":"http://purl.obolibrary.org/obo/MONDO_0007435"},{"id":"A94","pred":"mondo_id","subj":"T94","obj":"http://purl.obolibrary.org/obo/MONDO_0019018"},{"id":"A95","pred":"mondo_id","subj":"T95","obj":"http://purl.obolibrary.org/obo/MONDO_0005087"},{"id":"A96","pred":"mondo_id","subj":"T96","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A97","pred":"mondo_id","subj":"T97","obj":"http://purl.obolibrary.org/obo/MONDO_0011122"},{"id":"A98","pred":"mondo_id","subj":"T98","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A99","pred":"mondo_id","subj":"T99","obj":"http://purl.obolibrary.org/obo/MONDO_0006591"},{"id":"A100","pred":"mondo_id","subj":"T100","obj":"http://purl.obolibrary.org/obo/MONDO_0011122"},{"id":"A101","pred":"mondo_id","subj":"T101","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A102","pred":"mondo_id","subj":"T102","obj":"http://purl.obolibrary.org/obo/MONDO_0006873"},{"id":"A103","pred":"mondo_id","subj":"T103","obj":"http://purl.obolibrary.org/obo/MONDO_0011122"},{"id":"A104","pred":"mondo_id","subj":"T104","obj":"http://purl.obolibrary.org/obo/MONDO_0005550"},{"id":"A105","pred":"mondo_id","subj":"T105","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A106","pred":"mondo_id","subj":"T106","obj":"http://purl.obolibrary.org/obo/MONDO_0005550"}],"text":"Immune system, inflammation and COVID-19\nThe immune system protects the human body from infections by a series of pathogen (bacteria, viruses, fungi, parasites) [5]. A self-tolerance system prevents the immune response from damaging human tissues. The immune system is always active, carrying out surveillance. The defense to first exposure to the pathogen is represented by two complementary and cooperating functional divisions, the innate immune and, on the other hand, the adaptive immune response, that represents a response based on previous exposure [6]. The innate immune system is represented by dendritic cells, macrophages and neutrophils, with phagocytic activity, and by eosinophils, mast cells and natural killer cells, which release specific soluble antimicrobial factors. The innate immune system includes physical barriers, represented by interconnected epithelial cells (e.g. tight junctions and cellular interactions mediated by cadherin), epithelial cilia and the mucus layer of the respiratory, gastrointestinal and genitourinary epithelium. Moreover, soluble proteins and small bioactive molecules such as complement proteins, defensins and ficolins 1-3, pro-inflammatory cytokines, chemokines, lipid mediators of inflammation, membrane-bound receptors and cytoplasmic proteins are part of the innate immune system. Both innate and adaptive immunity is mediated by leukocytes. Lymphocytes circulate between the blood system and the lymphatic system, passing through the peripheral lymphoid organs, which includes the spleen, tonsils, appendix, lymph nodes and gut-associated lymphoid tissue (GALT). From a common lymphoid progenitor, four major populations of mature lymphocytes are derived, that belong to the adaptive immune system: of B lymphocytes (B cells) and T lymphocytes (T cells), natural killer (NK) cells, and NK-T cells. T-cells can be further categorized to cytotoxic T-cells (TC cells), helper T-cells (Th) and suppressor T-cells. The specific antigenic receptors of the adaptive response are represented by genes that code for an intact T cell receptor (TCR) and immunoglobulin genes (B cell antigen receptor; Ig). TCR is capable of binding the antigen processed by antigen-presenting cells (APC). Dendritic cells represent the most powerful class of APC, and express molecules of the major histocompatibility complex (MHC) of class I and II, necessary for the recognition of the antigen processed by TCR on T cells [7].\nFollowing the presentation of viral antigens via MHC II, the T helper CD4+ lymphocytes are activated and switch to the T helper 1 phenotype [8].\nThe activated T helper lymphocytes proliferate and release cytokines: after stimulation by antigen and APC, the Th0 cells begin to produce interleukin (IL)-2. Meanwhile, Th cells differentiate into Th1, Th2 and Th17 according to the nature of the cytokines present in the activation site: IL-12 produced by macrophages and type I Interferon (IFN) or NK cells induce differentiation towards Th1, IL-4 produced by NK1.1 + T cells, basophils or mast cells induce differentiation towards Th2, and IL-1b, IL-23, TGFβ and IL-6 induce differentiation towards Th17 [9]. Th17 cells produce IL-17 and IL-22, and antigen-induced Treg (iTreg).\nThe binding of the cytokine to its transmembrane cell surface receptor activates an intracellular signal transduction pathway, generally a Janus kinase (Jak), which, via a kinase cascade, phosphorylates its transcription protein (STAT). Phosphorylated STAT dimers and moves to the nucleus, initiating a new gene transcription. Mutation of STAT1 increases susceptibility to virus infections because it is involved in various signalling pathways, including IFN-α/β, IFN- γ, IFN-l, IL-2, IL-3, IL-6, IL-9, IL-10, IL-11, IL-12, IL-15, IL-21, IL-22, IL-26 and IL-27 [10], and chemokines of several types such as C-X-C motif chemokine ligand 10 (CXCL-10), Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted (RANTES)/Chemokine (C–C motif) ligand 5 (CCL-5), Monocyte Chemoattractant Protein-1 (MCP-1) [11]. IFN-γ promotes antigen-specific antibody production, increasing the activity of phagocytosis. In the meantime, PRRs trigger inflammatory signalling, with activation of transcription factors like nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). NFκB is the key transcriptional regulator of many pro-inflammatory cytokines, adhesion molecules, chemokines, growth factors and other mediators of inflammation, as tumour necrosis factor (TNF), interleukins 1 (IL-1β), 6 (IL-6), and 12 (IL-12), promotes cellular proliferation and protects against apoptosis providing a mechanism that determines chronic inflammation. The recognition of pathogens is achieved through the presence of pattern recognition receptors (PRRs) [12]. PRRs identify the microbe-associated molecular patterns (MAMPs), and defensive responses is activated. PRRs include Toll-like receptors (TLRs), that are able to recognize viral DNA, viral double-stranded RNA and viral single-stranded RNA. TLRs are expressed on macrophages, dendritic cells, neutrophils, eosinophils, epithelial cells and keratinocytes. In particular, intracellular TLR-7 and TLR-8 allow the innate recognition of the single-stranded RNA of coronaviruses [13]. Intracellular and extracellular PRRs recognized spike glycoprotein, of the coronavirus coat, starting the inflammatory process, through the NFκB pathway [14]. Moreover, Nucleotide-Binding Domain, Leucine-Rich Repeat (NLR) proteins have also been identified, and NALP3 (NACHT, LRR and PYD domains-containing protein 3) has a special function in the innate immune response [15]. The processes involved in antiviral immunity is shown in Fig. 1.\nFig. 1 Graphical representation of antiviral SARS-Coronavirus 2 immunity. B: B lymphocyte; CTL: cytotoxic; T lymphocyte; IFN: interferon; Ig: immunoglobulin; IL: interleukin; MHC: major histocompatibility class; NFκB: nuclear factor kappa-light- chain- enhancer of activated B cells; NK: natural killer cell; Th: helper T lymphocyte; TLR: Toll-like receptor; TNF: tumour necrosis factor\nNormal inflammation is self-limiting because the production of pro-inflammatory cytokines (Th1 cytokines) is followed almost immediately by the production of anti-inflammatory cytokines (Th2 cytokines; IL-1, IL-10, IL-13, etc.). Chronic inflammation seems to result when the initiating factors persist, or there is some sort of failure of the resolution process.\nDysfunction of the immune system and the loss of homeostatic equilibrium between TREG cells (IL- 10) and Th17 cells (IL-17) was observed in different pathological situations [16], and it is believed to increase the risk of viral infections, including SARS- coronavirus 2 (SARS-CoV-2) [14].\nSARS-CoV-2 is an enveloped positive-strand RNA virus in the family Coronaviridae, group 2b, which encodes the viral replicase and four structural proteins: spike (S), envelope (E) and membrane (M), present in the viral envelope, and nucleocapsid (N) [17].\nThe access route of SARS-CoV-2 is represented by a hydrophobic pocket of the extracellular catalytic domain of Angiotensin-converting enzyme 2 (ACE2) [18]. SARS-CoV peak S protein trimers bind ACE2, expressed in endothelial cells of the vasculature and in the epithelia of the lungs, intestine, heart, brain and kidney. SARS-CoV-2 enters the cell for endocytosis and membrane fusion. Once the virus has infected the cell, it follows a downregulation of ACE2 with a consequent local increase in the levels of Ang II, and the development of acute respiratory distress syndrome (ARDS) [19]. The role of ACE2 in the gut, for expression of neutral amino acid transporters, could explain diarrhoea and intestinal inflammation observed in COVID-19. Moreover, SARS-CoV2 protein E activates the NFκB inflammatory pathway with the consequent activation of MAPK p38, resulting in exacerbation of inflammation and immunopathology [20]. Following the SARS-CoV-2 infection, in the incubation stage and in the non-serious form of COVID-19, the immune system activates the specific adaptive immune response to eliminate the virus, which should be sufficient to block viral propagation and disease progression. The antiviral system functions well in the presence of general good health and an adequate genetic background. However, the presence of concomitant pathologies (obesity, cardiovascular diseases, diabetes, neurodegenerative diseases and cancer), malnutrition, and impaired immune response determine the spread of the virus and a massive destruction of the affected tissues, especially in organs that have high ACE2 expression [21]. As noted earlier, SARS-CoV-2 enters the cell via ACE2; that inactivates des-Arg bradykinin, which is a potent ligand of the bradykinin receptor type 1 (BDKRB1).This receptor, localized on endothelial cells, is up-regulated by inflammatory cytokines, which is unlike the B2 receptor, that is constituently expressed and is the receptor for bradykinin (BDK). BDK is produced from an inactive pre-protein kininogen through activation by the serine protease kallikrein; in addition, it is considered a potent regulator of blood pressure [22], because it induces vasodilation, natriuresis, and hypotension upon activation of the BDKRB2 receptor. BDK is strongly integrated with the RAS, and the BDK receptor signaling is increased by angiotensin’s action [23].\nInterestingly, ACE has a higher affinity for BDK [24] and therefore in conditions where ACE is low, the vasopressor system is moved toward a BDK-directed hypotensive axis. BDK takes part in the inflammatory response after injury and acts to induce pain via stimulation of the BDKRB1 receptor, which also causes neutrophil recruitment and a major vascular permeability [25, 26].\nDuring the infection, as long as the virus persists, there is dysfunction of ACE2 function, leading to the dysregulation of the kinin-kallikrein pathway and thus causing the angioedema [27]. Some evidence that the edema is bradykinin-generated includes resistance to corticosteroids, epinephrine, and antihistamines in the management of reducing the pulmonary edema in COVID-19 patients. In fact, the so called Bradykinin Storm is likely responsible for most of the observed COVID-19 symptoms.\nInflammation plays a fundamental role in the pathogenesis and progression of COVID-19, ranging from common colds to fatal cases of pneumonia due to the cytokine release syndrome (CRS) that affected patients, determining the severe conditions. In COVID-19 the homeostatic equilibrium between TREG cells (IL-10) and Th17 cells (IL-17) is broken: inflammatory cytokine levels (IL-1, TNF) are elevated in the lungs of COVID-19 patients, resulting in an increase in HA-synthase-2 (HAS2) in alveolar epithelial cells CD31+, EpCAM+ and fibroblasts. The imbalance between pro-inflammatory and anti-inflammatory cytokines, leads to the CRS, an excessive and damaging host inflammation [28]. As a consequence of CRS [29], due to a severe infection of SARS-CoV-2 of the respiratory epithelium, the ARDS was observed in COVID-19 [30]. Edema and an IL-1β mediated proinflammatory response were increased in the lung parenchyma. Macrophages and dendritic cells produce IL-1β through macro-molecular complexes called inflammasomes, including the major element present in the pulmonary tissue and the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome [20]. Following a precise stimulus, the activation and recruitment domain of caspase (ASC) and the catalytically inactive procaspase-1 assemble, the procaspase-1 turns into active caspase-1, the inactive pro-IL-1β matures in IL-1β and the NLRP3 inflammasome is activated. The NLRP3 inflammasomes and IL-1β driven proinflammatory cascades correlate with worsening of several respiratory diseases, including COVID-19.\nPatients affected by obesity showed a severe consequence of COVID-19 [31], due to the high concentrations of TNF-α, MCP-1 and IL-6 produced in the meantime by visceral and subcutaneous adipose tissue and by innate immunity [32]. Moreover, leptin, released by adipose tissue, helps to increase inflammatory milieu with a dysregulation of the immune response [33].\nThis umbrella review seeks to answer the question of whether a nutritional approach can be used to enhance the immune system’s response to obesity in obese patients affected by COVID-19.\nImmunonutrition has been based on the concept that malnutrition impairs immune function, used to modify inflammatory or immune responses. This concept may be applied to any situation in which a supply of specific nutrients is necessary to modify inflammatory or immune responses. Immunonutrients can promote patient recovery by inhibiting inflammatory responses and regulating immune function. Therefore, immunonutrition involves feeding enriched with various pharmaconutrients (arginine, glutamine, omega-3-fatty acids, ribonucleotides and certain trace elements and antioxidants compound, vitamins and minerals) to modulate inflammatory responses, the acquired immune response, and to improve patient outcomes [34].\nPersonalized immunonutrition for patients with obesity should be the first therapeutic choice to reduce the risk of infections and the disease course in COVID-19 patients. That therapeutic strategy could be effective in case of other potential epidemic infections. It would also allow a reduction of the enormous medical care cost supported by the National Health Service."}

{"project":"LitCovid-PD-CLO","denotations":[{"id":"T61","span":{"begin":0,"end":13},"obj":"http://purl.obolibrary.org/obo/UBERON_0002405"},{"id":"T62","span":{"begin":45,"end":58},"obj":"http://purl.obolibrary.org/obo/UBERON_0002405"},{"id":"T63","span":{"begin":72,"end":77},"obj":"http://purl.obolibrary.org/obo/NCBITaxon_9606"},{"id":"T64","span":{"begin":102,"end":103},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T65","span":{"begin":124,"end":132},"obj":"http://purl.obolibrary.org/obo/NCBITaxon_2"},{"id":"T66","span":{"begin":134,"end":141},"obj":"http://purl.obolibrary.org/obo/NCBITaxon_10239"},{"id":"T67","span":{"begin":166,"end":167},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T68","span":{"begin":233,"end":238},"obj":"http://purl.obolibrary.org/obo/NCBITaxon_9606"},{"id":"T69","span":{"begin":252,"end":265},"obj":"http://purl.obolibrary.org/obo/UBERON_0002405"},{"id":"T70","span":{"begin":276,"end":282},"obj":"http://purl.obolibrary.org/obo/CLO_0001658"},{"id":"T71","span":{"begin":519,"end":520},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T72","span":{"begin":573,"end":586},"obj":"http://purl.obolibrary.org/obo/UBERON_0002405"},{"id":"T73","span":{"begin":605,"end":620},"obj":"http://purl.obolibrary.org/obo/CL_0000451"},{"id":"T74","span":{"begin":656,"end":666},"obj":"http://purl.obolibrary.org/obo/CL_0000234"},{"id":"T75","span":{"begin":667,"end":675},"obj":"http://purl.obolibrary.org/obo/CLO_0001658"},{"id":"T76","span":{"begin":702,"end":707},"obj":"http://purl.obolibrary.org/obo/GO_0005623"},{"id":"T77","span":{"begin":712,"end":732},"obj":"http://purl.obolibrary.org/obo/CL_0000623"},{"id":"T78","span":{"begin":799,"end":812},"obj":"http://purl.obolibrary.org/obo/UBERON_0002405"},{"id":"T79","span":{"begin":871,"end":881},"obj":"http://purl.obolibrary.org/obo/CL_0000066"},{"id":"T80","span":{"begin":882,"end":887},"obj":"http://purl.obolibrary.org/obo/GO_0005623"},{"id":"T81","span":{"begin":900,"end":909},"obj":"http://purl.obolibrary.org/obo/UBERON_0007651"},{"id":"T82","span":{"begin":948,"end":956},"obj":"http://purl.obolibrary.org/obo/PR_000001327"},{"id":"T83","span":{"begin":959,"end":969},"obj":"http://purl.obolibrary.org/obo/CL_0000066"},{"id":"T84","span":{"begin":1051,"end":1061},"obj":"http://purl.obolibrary.org/obo/UBERON_0000483"},{"id":"T85","span":{"begin":1250,"end":1258},"obj":"http://purl.obolibrary.org/obo/UBERON_0000158"},{"id":"T86","span":{"begin":1323,"end":1336},"obj":"http://purl.obolibrary.org/obo/UBERON_0002405"},{"id":"T87","span":{"begin":1433,"end":1438},"obj":"http://purl.obolibrary.org/obo/UBERON_0000178"},{"id":"T88","span":{"begin":1433,"end":1438},"obj":"http://www.ebi.ac.uk/efo/EFO_0000296"},{"id":"T89","span":{"begin":1503,"end":1518},"obj":"http://purl.obolibrary.org/obo/UBERON_0004177"},{"id":"T90","span":{"begin":1539,"end":1545},"obj":"http://purl.obolibrary.org/obo/UBERON_0002106"},{"id":"T91","span":{"begin":1547,"end":1554},"obj":"http://purl.obolibrary.org/obo/UBERON_0002372"},{"id":"T92","span":{"begin":1566,"end":1577},"obj":"http://purl.obolibrary.org/obo/UBERON_0000029"},{"id":"T93","span":{"begin":1582,"end":1585},"obj":"http://purl.obolibrary.org/obo/UBERON_0001007"},{"id":"T94","span":{"begin":1582,"end":1585},"obj":"http://purl.obolibrary.org/obo/UBERON_0001555"},{"id":"T95","span":{"begin":1582,"end":1585},"obj":"http://www.ebi.ac.uk/efo/EFO_0000834"},{"id":"T96","span":{"begin":1597,"end":1612},"obj":"http://purl.obolibrary.org/obo/UBERON_0001744"},{"id":"T97","span":{"begin":1626,"end":1627},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T98","span":{"begin":1628,"end":1654},"obj":"http://purl.obolibrary.org/obo/CL_0000051"},{"id":"T99","span":{"begin":1742,"end":1755},"obj":"http://purl.obolibrary.org/obo/UBERON_0002405"},{"id":"T100","span":{"begin":1760,"end":1761},"obj":"http://purl.obolibrary.org/obo/CLO_0001021"},{"id":"T101","span":{"begin":1775,"end":1782},"obj":"http://purl.obolibrary.org/obo/CL_0000236"},{"id":"T102","span":{"begin":1803,"end":1810},"obj":"http://purl.obolibrary.org/obo/CL_0000084"},{"id":"T103","span":{"begin":1828,"end":1838},"obj":"http://purl.obolibrary.org/obo/CL_0000623"},{"id":"T104","span":{"begin":1847,"end":1854},"obj":"http://purl.obolibrary.org/obo/CL_0000084"},{"id":"T105","span":{"begin":1856,"end":1863},"obj":"http://purl.obolibrary.org/obo/CL_0000084"},{"id":"T106","span":{"begin":1904,"end":1911},"obj":"http://purl.obolibrary.org/obo/CL_0000084"},{"id":"T107","span":{"begin":1916,"end":1921},"obj":"http://purl.obolibrary.org/obo/GO_0005623"},{"id":"T108","span":{"begin":1924,"end":1938},"obj":"http://purl.obolibrary.org/obo/CL_0000912"},{"id":"T109","span":{"begin":1948,"end":1966},"obj":"http://purl.obolibrary.org/obo/CL_0000792"},{"id":"T110","span":{"begin":1948,"end":1966},"obj":"http://purl.obolibrary.org/obo/CL_0000815"},{"id":"T111","span":{"begin":2045,"end":2050},"obj":"http://purl.obolibrary.org/obo/OGG_0000000002"},{"id":"T112","span":{"begin":2075,"end":2081},"obj":"http://purl.obolibrary.org/obo/CL_0000084"},{"id":"T113","span":{"begin":2116,"end":2121},"obj":"http://purl.obolibrary.org/obo/OGG_0000000002"},{"id":"T114","span":{"begin":2123,"end":2129},"obj":"http://purl.obolibrary.org/obo/CL_0000236"},{"id":"T115","span":{"begin":2223,"end":2228},"obj":"http://purl.obolibrary.org/obo/GO_0005623"},{"id":"T116","span":{"begin":2236,"end":2251},"obj":"http://purl.obolibrary.org/obo/CL_0000451"},{"id":"T117","span":{"begin":2446,"end":2453},"obj":"http://purl.obolibrary.org/obo/CL_0000084"},{"id":"T118","span":{"begin":2529,"end":2532},"obj":"http://purl.obolibrary.org/obo/PR_000001004"},{"id":"T119","span":{"begin":2550,"end":2559},"obj":"http://purl.obolibrary.org/obo/CLO_0001658"},{"id":"T120","span":{"begin":2608,"end":2617},"obj":"http://purl.obolibrary.org/obo/CLO_0001658"},{"id":"T121","span":{"begin":2716,"end":2719},"obj":"http://purl.obolibrary.org/obo/CL_0000895"},{"id":"T122","span":{"begin":2720,"end":2725},"obj":"http://purl.obolibrary.org/obo/GO_0005623"},{"id":"T123","span":{"begin":2755,"end":2761},"obj":"http://purl.obolibrary.org/obo/PR_000001379"},{"id":"T124","span":{"begin":2777,"end":2782},"obj":"http://purl.obolibrary.org/obo/GO_0005623"},{"id":"T125","span":{"begin":2876,"end":2886},"obj":"http://purl.obolibrary.org/obo/CLO_0001658"},{"id":"T126","span":{"begin":2927,"end":2944},"obj":"http://purl.obolibrary.org/obo/PR_000024990"},{"id":"T127","span":{"begin":2954,"end":2962},"obj":"http://purl.obolibrary.org/obo/CL_0000623"},{"id":"T128","span":{"begin":3024,"end":3031},"obj":"http://purl.obolibrary.org/obo/CL_0000084"},{"id":"T129","span":{"begin":3051,"end":3056},"obj":"http://purl.obolibrary.org/obo/GO_0005623"},{"id":"T130","span":{"begin":3097,"end":3102},"obj":"http://purl.obolibrary.org/obo/PR_000001136"},{"id":"T131","span":{"begin":3171,"end":3176},"obj":"http://purl.obolibrary.org/obo/GO_0005623"},{"id":"T132","span":{"begin":3198,"end":3200},"obj":"http://purl.obolibrary.org/obo/CLO_0050507"},{"id":"T133","span":{"begin":3214,"end":3226},"obj":"http://purl.obolibrary.org/obo/CL_0000902"},{"id":"T134","span":{"begin":3228,"end":3233},"obj":"http://purl.obolibrary.org/obo/CL_0000902"},{"id":"T135","span":{"begin":3285,"end":3289},"obj":"http://purl.obolibrary.org/obo/GO_0005623"},{"id":"T136","span":{"begin":3307,"end":3316},"obj":"http://purl.obolibrary.org/obo/CLO_0001658"},{"id":"T137","span":{"begin":3334,"end":3340},"obj":"http://purl.obolibrary.org/obo/SO_0000418"},{"id":"T138","span":{"begin":3373,"end":3374},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T139","span":{"begin":3406,"end":3407},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T140","span":{"begin":3537,"end":3538},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T141","span":{"begin":3543,"end":3547},"obj":"http://purl.obolibrary.org/obo/OGG_0000000002"},{"id":"T142","span":{"begin":3609,"end":3614},"obj":"http://purl.obolibrary.org/obo/NCBITaxon_10239"},{"id":"T143","span":{"begin":3660,"end":3670},"obj":"http://purl.obolibrary.org/obo/SO_0000418"},{"id":"T144","span":{"begin":3715,"end":3719},"obj":"http://purl.obolibrary.org/obo/PR_000001379"},{"id":"T145","span":{"begin":3721,"end":3725},"obj":"http://purl.obolibrary.org/obo/PR_000001387"},{"id":"T146","span":{"begin":3746,"end":3751},"obj":"http://purl.obolibrary.org/obo/CLO_0053702"},{"id":"T147","span":{"begin":3777,"end":3779},"obj":"http://purl.obolibrary.org/obo/CLO_0050507"},{"id":"T148","span":{"begin":3794,"end":3796},"obj":"http://purl.obolibrary.org/obo/CLO_0050509"},{"id":"T149","span":{"begin":3845,"end":3848},"obj":"http://purl.obolibrary.org/obo/CLO_0009645"},{"id":"T150","span":{"begin":3845,"end":3848},"obj":"http://purl.obolibrary.org/obo/CLO_0050824"},{"id":"T151","span":{"begin":3901,"end":3911},"obj":"http://purl.obolibrary.org/obo/CLO_0001658"},{"id":"T152","span":{"begin":3920,"end":3926},"obj":"http://purl.obolibrary.org/obo/CL_0000084"},{"id":"T153","span":{"begin":4010,"end":4018},"obj":"http://purl.obolibrary.org/obo/CL_0000576"},{"id":"T154","span":{"begin":4054,"end":4056},"obj":"http://purl.obolibrary.org/obo/CLO_0053733"},{"id":"T155","span":{"begin":4127,"end":4135},"obj":"http://purl.obolibrary.org/obo/CLO_0001658"},{"id":"T156","span":{"begin":4196,"end":4206},"obj":"http://purl.obolibrary.org/obo/SO_0000418"},{"id":"T157","span":{"begin":4213,"end":4223},"obj":"http://purl.obolibrary.org/obo/CLO_0001658"},{"id":"T158","span":{"begin":4299,"end":4308},"obj":"http://purl.obolibrary.org/obo/CLO_0001658"},{"id":"T159","span":{"begin":4309,"end":4316},"obj":"http://purl.obolibrary.org/obo/CL_0000236"},{"id":"T160","span":{"begin":4321,"end":4322},"obj":"http://purl.obolibrary.org/obo/CLO_0001021"},{"id":"T161","span":{"begin":4328,"end":4329},"obj":"http://purl.obolibrary.org/obo/CLO_0001021"},{"id":"T162","span":{"begin":4520,"end":4534},"obj":"http://purl.obolibrary.org/obo/PR_000001091"},{"id":"T163","span":{"begin":4643,"end":4644},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T164","span":{"begin":4893,"end":4902},"obj":"http://purl.obolibrary.org/obo/CLO_0001658"},{"id":"T165","span":{"begin":5075,"end":5090},"obj":"http://purl.obolibrary.org/obo/CL_0000451"},{"id":"T166","span":{"begin":5118,"end":5128},"obj":"http://purl.obolibrary.org/obo/CL_0000066"},{"id":"T167","span":{"begin":5129,"end":5134},"obj":"http://purl.obolibrary.org/obo/GO_0005623"},{"id":"T168","span":{"begin":5139,"end":5152},"obj":"http://purl.obolibrary.org/obo/CL_0000312"},{"id":"T169","span":{"begin":5421,"end":5422},"obj":"http://purl.obolibrary.org/obo/CLO_0001021"},{"id":"T170","span":{"begin":5596,"end":5599},"obj":"http://purl.obolibrary.org/obo/CLO_0051582"},{"id":"T171","span":{"begin":5600,"end":5601},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T172","span":{"begin":5794,"end":5798},"obj":"http://purl.obolibrary.org/obo/CLO_0001869"},{"id":"T173","span":{"begin":5935,"end":5936},"obj":"http://purl.obolibrary.org/obo/CLO_0001021"},{"id":"T174","span":{"begin":5985,"end":5994},"obj":"http://purl.obolibrary.org/obo/CLO_0001658"},{"id":"T175","span":{"begin":5995,"end":6002},"obj":"http://purl.obolibrary.org/obo/CL_0000236"},{"id":"T176","span":{"begin":6008,"end":6027},"obj":"http://purl.obolibrary.org/obo/CL_0000623"},{"id":"T177","span":{"begin":6033,"end":6052},"obj":"http://purl.obolibrary.org/obo/CL_0000912"},{"id":"T178","span":{"begin":6489,"end":6502},"obj":"http://purl.obolibrary.org/obo/UBERON_0002405"},{"id":"T179","span":{"begin":6551,"end":6555},"obj":"http://purl.obolibrary.org/obo/CL_0000792"},{"id":"T180","span":{"begin":6556,"end":6561},"obj":"http://purl.obolibrary.org/obo/GO_0005623"},{"id":"T181","span":{"begin":6580,"end":6585},"obj":"http://purl.obolibrary.org/obo/GO_0005623"},{"id":"T182","span":{"begin":6807,"end":6812},"obj":"http://purl.obolibrary.org/obo/NCBITaxon_10239"},{"id":"T183","span":{"begin":6944,"end":6952},"obj":"http://purl.obolibrary.org/obo/UBERON_0000158"},{"id":"T184","span":{"begin":7065,"end":7066},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T185","span":{"begin":7167,"end":7169},"obj":"http://purl.obolibrary.org/obo/CLO_0050510"},{"id":"T186","span":{"begin":7228,"end":7245},"obj":"http://purl.obolibrary.org/obo/CL_0000115"},{"id":"T187","span":{"begin":7293,"end":7298},"obj":"http://www.ebi.ac.uk/efo/EFO_0000934"},{"id":"T188","span":{"begin":7300,"end":7309},"obj":"http://purl.obolibrary.org/obo/UBERON_0000160"},{"id":"T189","span":{"begin":7300,"end":7309},"obj":"http://www.ebi.ac.uk/efo/EFO_0000834"},{"id":"T190","span":{"begin":7311,"end":7316},"obj":"http://purl.obolibrary.org/obo/UBERON_0000948"},{"id":"T191","span":{"begin":7311,"end":7316},"obj":"http://purl.obolibrary.org/obo/UBERON_0007100"},{"id":"T192","span":{"begin":7311,"end":7316},"obj":"http://purl.obolibrary.org/obo/UBERON_0015228"},{"id":"T193","span":{"begin":7311,"end":7316},"obj":"http://www.ebi.ac.uk/efo/EFO_0000815"},{"id":"T194","span":{"begin":7318,"end":7323},"obj":"http://purl.obolibrary.org/obo/UBERON_0000955"},{"id":"T195","span":{"begin":7318,"end":7323},"obj":"http://www.ebi.ac.uk/efo/EFO_0000302"},{"id":"T196","span":{"begin":7328,"end":7334},"obj":"http://purl.obolibrary.org/obo/UBERON_0002113"},{"id":"T197","span":{"begin":7328,"end":7334},"obj":"http://www.ebi.ac.uk/efo/EFO_0000927"},{"id":"T198","span":{"begin":7328,"end":7334},"obj":"http://www.ebi.ac.uk/efo/EFO_0000929"},{"id":"T199","span":{"begin":7358,"end":7362},"obj":"http://purl.obolibrary.org/obo/GO_0005623"},{"id":"T200","span":{"begin":7383,"end":7391},"obj":"http://purl.obolibrary.org/obo/UBERON_0000158"},{"id":"T201","span":{"begin":7409,"end":7414},"obj":"http://purl.obolibrary.org/obo/NCBITaxon_10239"},{"id":"T202","span":{"begin":7415,"end":7418},"obj":"http://purl.obolibrary.org/obo/CLO_0051582"},{"id":"T203","span":{"begin":7432,"end":7436},"obj":"http://purl.obolibrary.org/obo/GO_0005623"},{"id":"T204","span":{"begin":7449,"end":7450},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T205","span":{"begin":7479,"end":7480},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T206","span":{"begin":7628,"end":7631},"obj":"http://purl.obolibrary.org/obo/UBERON_0001007"},{"id":"T207","span":{"begin":7628,"end":7631},"obj":"http://purl.obolibrary.org/obo/UBERON_0001555"},{"id":"T208","span":{"begin":7628,"end":7631},"obj":"http://www.ebi.ac.uk/efo/EFO_0000834"},{"id":"T209","span":{"begin":7712,"end":7722},"obj":"http://purl.obolibrary.org/obo/UBERON_0000160"},{"id":"T210","span":{"begin":7712,"end":7722},"obj":"http://www.ebi.ac.uk/efo/EFO_0000834"},{"id":"T211","span":{"begin":7788,"end":7797},"obj":"http://purl.obolibrary.org/obo/CLO_0001658"},{"id":"T212","span":{"begin":7805,"end":7806},"obj":"http://purl.obolibrary.org/obo/CLO_0001021"},{"id":"T213","span":{"begin":7848,"end":7858},"obj":"http://purl.obolibrary.org/obo/CLO_0001658"},{"id":"T214","span":{"begin":8045,"end":8058},"obj":"http://purl.obolibrary.org/obo/UBERON_0002405"},{"id":"T215","span":{"begin":8059,"end":8068},"obj":"http://purl.obolibrary.org/obo/CLO_0001658"},{"id":"T216","span":{"begin":8124,"end":8129},"obj":"http://purl.obolibrary.org/obo/NCBITaxon_10239"},{"id":"T217","span":{"begin":8526,"end":8531},"obj":"http://purl.obolibrary.org/obo/NCBITaxon_10239"},{"id":"T218","span":{"begin":8536,"end":8537},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T219","span":{"begin":8597,"end":8603},"obj":"http://purl.obolibrary.org/obo/UBERON_0003103"},{"id":"T220","span":{"begin":8681,"end":8685},"obj":"http://purl.obolibrary.org/obo/GO_0005623"},{"id":"T221","span":{"begin":8742,"end":8743},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T222","span":{"begin":8829,"end":8846},"obj":"http://purl.obolibrary.org/obo/CL_0000115"},{"id":"T223","span":{"begin":9061,"end":9071},"obj":"http://purl.obolibrary.org/obo/CLO_0001658"},{"id":"T224","span":{"begin":9137,"end":9138},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T225","span":{"begin":9159,"end":9164},"obj":"http://purl.obolibrary.org/obo/UBERON_0000178"},{"id":"T226","span":{"begin":9159,"end":9164},"obj":"http://www.ebi.ac.uk/efo/EFO_0000296"},{"id":"T227","span":{"begin":9175,"end":9177},"obj":"http://purl.obolibrary.org/obo/CLO_0050507"},{"id":"T228","span":{"begin":9247,"end":9257},"obj":"http://purl.obolibrary.org/obo/CLO_0001658"},{"id":"T229","span":{"begin":9344,"end":9353},"obj":"http://purl.obolibrary.org/obo/SO_0000418"},{"id":"T230","span":{"begin":9416,"end":9419},"obj":"http://purl.obolibrary.org/obo/CLO_0051582"},{"id":"T231","span":{"begin":9420,"end":9421},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T232","span":{"begin":9536,"end":9537},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T233","span":{"begin":9735,"end":9736},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T234","span":{"begin":9812,"end":9817},"obj":"http://purl.obolibrary.org/obo/NCBITaxon_10239"},{"id":"T235","span":{"begin":9961,"end":9963},"obj":"http://purl.obolibrary.org/obo/CLO_0050509"},{"id":"T236","span":{"begin":10288,"end":10289},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T237","span":{"begin":10560,"end":10564},"obj":"http://purl.obolibrary.org/obo/CL_0000792"},{"id":"T238","span":{"begin":10565,"end":10570},"obj":"http://purl.obolibrary.org/obo/GO_0005623"},{"id":"T239","span":{"begin":10588,"end":10593},"obj":"http://purl.obolibrary.org/obo/GO_0005623"},{"id":"T240","span":{"begin":10674,"end":10679},"obj":"http://www.ebi.ac.uk/efo/EFO_0000934"},{"id":"T241","span":{"begin":10763,"end":10773},"obj":"http://purl.obolibrary.org/obo/CL_0000066"},{"id":"T242","span":{"begin":10774,"end":10779},"obj":"http://purl.obolibrary.org/obo/GO_0005623"},{"id":"T243","span":{"begin":10780,"end":10784},"obj":"http://purl.obolibrary.org/obo/CLO_0053435"},{"id":"T244","span":{"begin":10798,"end":10809},"obj":"http://purl.obolibrary.org/obo/CL_0000057"},{"id":"T245","span":{"begin":10954,"end":10955},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T246","span":{"begin":10988,"end":10989},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T247","span":{"begin":11028,"end":11050},"obj":"http://purl.obolibrary.org/obo/UBERON_0004802"},{"id":"T248","span":{"begin":11167,"end":11171},"obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"T249","span":{"begin":11167,"end":11171},"obj":"http://www.ebi.ac.uk/efo/EFO_0000934"},{"id":"T250","span":{"begin":11200,"end":11215},"obj":"http://purl.obolibrary.org/obo/CL_0000451"},{"id":"T251","span":{"begin":11487,"end":11488},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T252","span":{"begin":11511,"end":11521},"obj":"http://purl.obolibrary.org/obo/CLO_0001658"},{"id":"T253","span":{"begin":11644,"end":11650},"obj":"http://purl.obolibrary.org/obo/CLO_0001658"},{"id":"T254","span":{"begin":11732,"end":11741},"obj":"http://purl.obolibrary.org/obo/CLO_0001658"},{"id":"T255","span":{"begin":11923,"end":11924},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T256","span":{"begin":12059,"end":12086},"obj":"http://purl.obolibrary.org/obo/UBERON_0002190"},{"id":"T257","span":{"begin":12146,"end":12160},"obj":"http://purl.obolibrary.org/obo/UBERON_0001013"},{"id":"T258","span":{"begin":12205,"end":12206},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T259","span":{"begin":12311,"end":12312},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T260","span":{"begin":12361,"end":12376},"obj":"http://purl.obolibrary.org/obo/UBERON_0002405"},{"id":"T261","span":{"begin":12453,"end":12456},"obj":"http://purl.obolibrary.org/obo/CLO_0051582"},{"id":"T262","span":{"begin":12629,"end":12630},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T263","span":{"begin":13150,"end":13152},"obj":"http://purl.obolibrary.org/obo/CLO_0001302"},{"id":"T264","span":{"begin":13440,"end":13441},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"}],"text":"Immune system, inflammation and COVID-19\nThe immune system protects the human body from infections by a series of pathogen (bacteria, viruses, fungi, parasites) [5]. A self-tolerance system prevents the immune response from damaging human tissues. The immune system is always active, carrying out surveillance. The defense to first exposure to the pathogen is represented by two complementary and cooperating functional divisions, the innate immune and, on the other hand, the adaptive immune response, that represents a response based on previous exposure [6]. The innate immune system is represented by dendritic cells, macrophages and neutrophils, with phagocytic activity, and by eosinophils, mast cells and natural killer cells, which release specific soluble antimicrobial factors. The innate immune system includes physical barriers, represented by interconnected epithelial cells (e.g. tight junctions and cellular interactions mediated by cadherin), epithelial cilia and the mucus layer of the respiratory, gastrointestinal and genitourinary epithelium. Moreover, soluble proteins and small bioactive molecules such as complement proteins, defensins and ficolins 1-3, pro-inflammatory cytokines, chemokines, lipid mediators of inflammation, membrane-bound receptors and cytoplasmic proteins are part of the innate immune system. Both innate and adaptive immunity is mediated by leukocytes. Lymphocytes circulate between the blood system and the lymphatic system, passing through the peripheral lymphoid organs, which includes the spleen, tonsils, appendix, lymph nodes and gut-associated lymphoid tissue (GALT). From a common lymphoid progenitor, four major populations of mature lymphocytes are derived, that belong to the adaptive immune system: of B lymphocytes (B cells) and T lymphocytes (T cells), natural killer (NK) cells, and NK-T cells. T-cells can be further categorized to cytotoxic T-cells (TC cells), helper T-cells (Th) and suppressor T-cells. The specific antigenic receptors of the adaptive response are represented by genes that code for an intact T cell receptor (TCR) and immunoglobulin genes (B cell antigen receptor; Ig). TCR is capable of binding the antigen processed by antigen-presenting cells (APC). Dendritic cells represent the most powerful class of APC, and express molecules of the major histocompatibility complex (MHC) of class I and II, necessary for the recognition of the antigen processed by TCR on T cells [7].\nFollowing the presentation of viral antigens via MHC II, the T helper CD4+ lymphocytes are activated and switch to the T helper 1 phenotype [8].\nThe activated T helper lymphocytes proliferate and release cytokines: after stimulation by antigen and APC, the Th0 cells begin to produce interleukin (IL)-2. Meanwhile, Th cells differentiate into Th1, Th2 and Th17 according to the nature of the cytokines present in the activation site: IL-12 produced by macrophages and type I Interferon (IFN) or NK cells induce differentiation towards Th1, IL-4 produced by NK1.1 + T cells, basophils or mast cells induce differentiation towards Th2, and IL-1b, IL-23, TGFβ and IL-6 induce differentiation towards Th17 [9]. Th17 cells produce IL-17 and IL-22, and antigen-induced Treg (iTreg).\nThe binding of the cytokine to its transmembrane cell surface receptor activates an intracellular signal transduction pathway, generally a Janus kinase (Jak), which, via a kinase cascade, phosphorylates its transcription protein (STAT). Phosphorylated STAT dimers and moves to the nucleus, initiating a new gene transcription. Mutation of STAT1 increases susceptibility to virus infections because it is involved in various signalling pathways, including IFN-α/β, IFN- γ, IFN-l, IL-2, IL-3, IL-6, IL-9, IL-10, IL-11, IL-12, IL-15, IL-21, IL-22, IL-26 and IL-27 [10], and chemokines of several types such as C-X-C motif chemokine ligand 10 (CXCL-10), Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted (RANTES)/Chemokine (C–C motif) ligand 5 (CCL-5), Monocyte Chemoattractant Protein-1 (MCP-1) [11]. IFN-γ promotes antigen-specific antibody production, increasing the activity of phagocytosis. In the meantime, PRRs trigger inflammatory signalling, with activation of transcription factors like nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). NFκB is the key transcriptional regulator of many pro-inflammatory cytokines, adhesion molecules, chemokines, growth factors and other mediators of inflammation, as tumour necrosis factor (TNF), interleukins 1 (IL-1β), 6 (IL-6), and 12 (IL-12), promotes cellular proliferation and protects against apoptosis providing a mechanism that determines chronic inflammation. The recognition of pathogens is achieved through the presence of pattern recognition receptors (PRRs) [12]. PRRs identify the microbe-associated molecular patterns (MAMPs), and defensive responses is activated. PRRs include Toll-like receptors (TLRs), that are able to recognize viral DNA, viral double-stranded RNA and viral single-stranded RNA. TLRs are expressed on macrophages, dendritic cells, neutrophils, eosinophils, epithelial cells and keratinocytes. In particular, intracellular TLR-7 and TLR-8 allow the innate recognition of the single-stranded RNA of coronaviruses [13]. Intracellular and extracellular PRRs recognized spike glycoprotein, of the coronavirus coat, starting the inflammatory process, through the NFκB pathway [14]. Moreover, Nucleotide-Binding Domain, Leucine-Rich Repeat (NLR) proteins have also been identified, and NALP3 (NACHT, LRR and PYD domains-containing protein 3) has a special function in the innate immune response [15]. The processes involved in antiviral immunity is shown in Fig. 1.\nFig. 1 Graphical representation of antiviral SARS-Coronavirus 2 immunity. B: B lymphocyte; CTL: cytotoxic; T lymphocyte; IFN: interferon; Ig: immunoglobulin; IL: interleukin; MHC: major histocompatibility class; NFκB: nuclear factor kappa-light- chain- enhancer of activated B cells; NK: natural killer cell; Th: helper T lymphocyte; TLR: Toll-like receptor; TNF: tumour necrosis factor\nNormal inflammation is self-limiting because the production of pro-inflammatory cytokines (Th1 cytokines) is followed almost immediately by the production of anti-inflammatory cytokines (Th2 cytokines; IL-1, IL-10, IL-13, etc.). Chronic inflammation seems to result when the initiating factors persist, or there is some sort of failure of the resolution process.\nDysfunction of the immune system and the loss of homeostatic equilibrium between TREG cells (IL- 10) and Th17 cells (IL-17) was observed in different pathological situations [16], and it is believed to increase the risk of viral infections, including SARS- coronavirus 2 (SARS-CoV-2) [14].\nSARS-CoV-2 is an enveloped positive-strand RNA virus in the family Coronaviridae, group 2b, which encodes the viral replicase and four structural proteins: spike (S), envelope (E) and membrane (M), present in the viral envelope, and nucleocapsid (N) [17].\nThe access route of SARS-CoV-2 is represented by a hydrophobic pocket of the extracellular catalytic domain of Angiotensin-converting enzyme 2 (ACE2) [18]. SARS-CoV peak S protein trimers bind ACE2, expressed in endothelial cells of the vasculature and in the epithelia of the lungs, intestine, heart, brain and kidney. SARS-CoV-2 enters the cell for endocytosis and membrane fusion. Once the virus has infected the cell, it follows a downregulation of ACE2 with a consequent local increase in the levels of Ang II, and the development of acute respiratory distress syndrome (ARDS) [19]. The role of ACE2 in the gut, for expression of neutral amino acid transporters, could explain diarrhoea and intestinal inflammation observed in COVID-19. Moreover, SARS-CoV2 protein E activates the NFκB inflammatory pathway with the consequent activation of MAPK p38, resulting in exacerbation of inflammation and immunopathology [20]. Following the SARS-CoV-2 infection, in the incubation stage and in the non-serious form of COVID-19, the immune system activates the specific adaptive immune response to eliminate the virus, which should be sufficient to block viral propagation and disease progression. The antiviral system functions well in the presence of general good health and an adequate genetic background. However, the presence of concomitant pathologies (obesity, cardiovascular diseases, diabetes, neurodegenerative diseases and cancer), malnutrition, and impaired immune response determine the spread of the virus and a massive destruction of the affected tissues, especially in organs that have high ACE2 expression [21]. As noted earlier, SARS-CoV-2 enters the cell via ACE2; that inactivates des-Arg bradykinin, which is a potent ligand of the bradykinin receptor type 1 (BDKRB1).This receptor, localized on endothelial cells, is up-regulated by inflammatory cytokines, which is unlike the B2 receptor, that is constituently expressed and is the receptor for bradykinin (BDK). BDK is produced from an inactive pre-protein kininogen through activation by the serine protease kallikrein; in addition, it is considered a potent regulator of blood pressure [22], because it induces vasodilation, natriuresis, and hypotension upon activation of the BDKRB2 receptor. BDK is strongly integrated with the RAS, and the BDK receptor signaling is increased by angiotensin’s action [23].\nInterestingly, ACE has a higher affinity for BDK [24] and therefore in conditions where ACE is low, the vasopressor system is moved toward a BDK-directed hypotensive axis. BDK takes part in the inflammatory response after injury and acts to induce pain via stimulation of the BDKRB1 receptor, which also causes neutrophil recruitment and a major vascular permeability [25, 26].\nDuring the infection, as long as the virus persists, there is dysfunction of ACE2 function, leading to the dysregulation of the kinin-kallikrein pathway and thus causing the angioedema [27]. Some evidence that the edema is bradykinin-generated includes resistance to corticosteroids, epinephrine, and antihistamines in the management of reducing the pulmonary edema in COVID-19 patients. In fact, the so called Bradykinin Storm is likely responsible for most of the observed COVID-19 symptoms.\nInflammation plays a fundamental role in the pathogenesis and progression of COVID-19, ranging from common colds to fatal cases of pneumonia due to the cytokine release syndrome (CRS) that affected patients, determining the severe conditions. In COVID-19 the homeostatic equilibrium between TREG cells (IL-10) and Th17 cells (IL-17) is broken: inflammatory cytokine levels (IL-1, TNF) are elevated in the lungs of COVID-19 patients, resulting in an increase in HA-synthase-2 (HAS2) in alveolar epithelial cells CD31+, EpCAM+ and fibroblasts. The imbalance between pro-inflammatory and anti-inflammatory cytokines, leads to the CRS, an excessive and damaging host inflammation [28]. As a consequence of CRS [29], due to a severe infection of SARS-CoV-2 of the respiratory epithelium, the ARDS was observed in COVID-19 [30]. Edema and an IL-1β mediated proinflammatory response were increased in the lung parenchyma. Macrophages and dendritic cells produce IL-1β through macro-molecular complexes called inflammasomes, including the major element present in the pulmonary tissue and the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome [20]. Following a precise stimulus, the activation and recruitment domain of caspase (ASC) and the catalytically inactive procaspase-1 assemble, the procaspase-1 turns into active caspase-1, the inactive pro-IL-1β matures in IL-1β and the NLRP3 inflammasome is activated. The NLRP3 inflammasomes and IL-1β driven proinflammatory cascades correlate with worsening of several respiratory diseases, including COVID-19.\nPatients affected by obesity showed a severe consequence of COVID-19 [31], due to the high concentrations of TNF-α, MCP-1 and IL-6 produced in the meantime by visceral and subcutaneous adipose tissue and by innate immunity [32]. Moreover, leptin, released by adipose tissue, helps to increase inflammatory milieu with a dysregulation of the immune response [33].\nThis umbrella review seeks to answer the question of whether a nutritional approach can be used to enhance the immune system’s response to obesity in obese patients affected by COVID-19.\nImmunonutrition has been based on the concept that malnutrition impairs immune function, used to modify inflammatory or immune responses. This concept may be applied to any situation in which a supply of specific nutrients is necessary to modify inflammatory or immune responses. Immunonutrients can promote patient recovery by inhibiting inflammatory responses and regulating immune function. Therefore, immunonutrition involves feeding enriched with various pharmaconutrients (arginine, glutamine, omega-3-fatty acids, ribonucleotides and certain trace elements and antioxidants compound, vitamins and minerals) to modulate inflammatory responses, the acquired immune response, and to improve patient outcomes [34].\nPersonalized immunonutrition for patients with obesity should be the first therapeutic choice to reduce the risk of infections and the disease course in COVID-19 patients. That therapeutic strategy could be effective in case of other potential epidemic infections. It would also allow a reduction of the enormous medical care cost supported by the National Health Service."}

{"project":"LitCovid-PD-CHEBI","denotations":[{"id":"T16","span":{"begin":765,"end":778},"obj":"Chemical"},{"id":"T17","span":{"begin":1081,"end":1089},"obj":"Chemical"},{"id":"T18","span":{"begin":1110,"end":1119},"obj":"Chemical"},{"id":"T19","span":{"begin":1139,"end":1147},"obj":"Chemical"},{"id":"T20","span":{"begin":1149,"end":1158},"obj":"Chemical"},{"id":"T21","span":{"begin":1217,"end":1222},"obj":"Chemical"},{"id":"T22","span":{"begin":1291,"end":1299},"obj":"Chemical"},{"id":"T23","span":{"begin":1940,"end":1942},"obj":"Chemical"},{"id":"T24","span":{"begin":2130,"end":2137},"obj":"Chemical"},{"id":"T25","span":{"begin":2183,"end":2190},"obj":"Chemical"},{"id":"T26","span":{"begin":2204,"end":2211},"obj":"Chemical"},{"id":"T27","span":{"begin":2230,"end":2233},"obj":"Chemical"},{"id":"T28","span":{"begin":2289,"end":2292},"obj":"Chemical"},{"id":"T29","span":{"begin":2306,"end":2315},"obj":"Chemical"},{"id":"T30","span":{"begin":2377,"end":2379},"obj":"Chemical"},{"id":"T31","span":{"begin":2418,"end":2425},"obj":"Chemical"},{"id":"T32","span":{"begin":2495,"end":2503},"obj":"Chemical"},{"id":"T33","span":{"begin":2512,"end":2514},"obj":"Chemical"},{"id":"T34","span":{"begin":2695,"end":2702},"obj":"Chemical"},{"id":"T35","span":{"begin":2707,"end":2710},"obj":"Chemical"},{"id":"T36","span":{"begin":2756,"end":2758},"obj":"Chemical"},{"id":"T38","span":{"begin":2774,"end":2776},"obj":"Chemical"},{"id":"T39","span":{"begin":2893,"end":2895},"obj":"Chemical"},{"id":"T41","span":{"begin":2999,"end":3001},"obj":"Chemical"},{"id":"T43","span":{"begin":3097,"end":3099},"obj":"Chemical"},{"id":"T45","span":{"begin":3104,"end":3106},"obj":"Chemical"},{"id":"T47","span":{"begin":3120,"end":3122},"obj":"Chemical"},{"id":"T49","span":{"begin":3185,"end":3187},"obj":"Chemical"},{"id":"T51","span":{"begin":3195,"end":3197},"obj":"Chemical"},{"id":"T53","span":{"begin":3206,"end":3213},"obj":"Chemical"},{"id":"T54","span":{"begin":3457,"end":3464},"obj":"Chemical"},{"id":"T55","span":{"begin":3517,"end":3524},"obj":"Chemical"},{"id":"T56","span":{"begin":3715,"end":3717},"obj":"Chemical"},{"id":"T58","span":{"begin":3721,"end":3723},"obj":"Chemical"},{"id":"T60","span":{"begin":3727,"end":3729},"obj":"Chemical"},{"id":"T62","span":{"begin":3733,"end":3735},"obj":"Chemical"},{"id":"T64","span":{"begin":3739,"end":3741},"obj":"Chemical"},{"id":"T66","span":{"begin":3746,"end":3748},"obj":"Chemical"},{"id":"T68","span":{"begin":3753,"end":3755},"obj":"Chemical"},{"id":"T70","span":{"begin":3760,"end":3762},"obj":"Chemical"},{"id":"T72","span":{"begin":3767,"end":3769},"obj":"Chemical"},{"id":"T74","span":{"begin":3774,"end":3776},"obj":"Chemical"},{"id":"T76","span":{"begin":3781,"end":3783},"obj":"Chemical"},{"id":"T78","span":{"begin":3791,"end":3793},"obj":"Chemical"},{"id":"T80","span":{"begin":3855,"end":3874},"obj":"Chemical"},{"id":"T81","span":{"begin":3865,"end":3871},"obj":"Chemical"},{"id":"T82","span":{"begin":3992,"end":3998},"obj":"Chemical"},{"id":"T83","span":{"begin":4002,"end":4005},"obj":"Chemical"},{"id":"T84","span":{"begin":4035,"end":4042},"obj":"Chemical"},{"id":"T85","span":{"begin":4046,"end":4049},"obj":"Chemical"},{"id":"T87","span":{"begin":4074,"end":4081},"obj":"Chemical"},{"id":"T88","span":{"begin":4318,"end":4320},"obj":"Chemical"},{"id":"T91","span":{"begin":4325,"end":4327},"obj":"Chemical"},{"id":"T94","span":{"begin":4412,"end":4421},"obj":"Chemical"},{"id":"T95","span":{"begin":4520,"end":4532},"obj":"Chemical"},{"id":"T96","span":{"begin":4536,"end":4538},"obj":"Chemical"},{"id":"T98","span":{"begin":4547,"end":4549},"obj":"Chemical"},{"id":"T100","span":{"begin":4562,"end":4564},"obj":"Chemical"},{"id":"T102","span":{"begin":4978,"end":4981},"obj":"Chemical"},{"id":"T103","span":{"begin":4989,"end":5008},"obj":"Chemical"},{"id":"T104","span":{"begin":5332,"end":5344},"obj":"Chemical"},{"id":"T105","span":{"begin":5418,"end":5420},"obj":"Chemical"},{"id":"T108","span":{"begin":5447,"end":5457},"obj":"Chemical"},{"id":"T109","span":{"begin":5500,"end":5508},"obj":"Chemical"},{"id":"T110","span":{"begin":5585,"end":5592},"obj":"Chemical"},{"id":"T111","span":{"begin":5681,"end":5690},"obj":"Chemical"},{"id":"T112","span":{"begin":5755,"end":5764},"obj":"Chemical"},{"id":"T113","span":{"begin":5846,"end":5856},"obj":"Chemical"},{"id":"T114","span":{"begin":5878,"end":5880},"obj":"Chemical"},{"id":"T116","span":{"begin":5932,"end":5934},"obj":"Chemical"},{"id":"T119","span":{"begin":6029,"end":6031},"obj":"Chemical"},{"id":"T120","span":{"begin":6309,"end":6311},"obj":"Chemical"},{"id":"T122","span":{"begin":6315,"end":6317},"obj":"Chemical"},{"id":"T124","span":{"begin":6322,"end":6324},"obj":"Chemical"},{"id":"T126","span":{"begin":6563,"end":6565},"obj":"Chemical"},{"id":"T128","span":{"begin":6587,"end":6589},"obj":"Chemical"},{"id":"T130","span":{"begin":6842,"end":6847},"obj":"Chemical"},{"id":"T131","span":{"begin":6906,"end":6914},"obj":"Chemical"},{"id":"T132","span":{"begin":7127,"end":7138},"obj":"Chemical"},{"id":"T133","span":{"begin":7188,"end":7195},"obj":"Chemical"},{"id":"T134","span":{"begin":7528,"end":7530},"obj":"Chemical"},{"id":"T135","span":{"begin":7659,"end":7669},"obj":"Chemical"},{"id":"T136","span":{"begin":7659,"end":7664},"obj":"Chemical"},{"id":"T137","span":{"begin":7665,"end":7669},"obj":"Chemical"},{"id":"T138","span":{"begin":7778,"end":7785},"obj":"Chemical"},{"id":"T139","span":{"begin":7802,"end":7804},"obj":"Chemical"},{"id":"T142","span":{"begin":8214,"end":8223},"obj":"Chemical"},{"id":"T143","span":{"begin":8717,"end":8720},"obj":"Chemical"},{"id":"T145","span":{"begin":8721,"end":8731},"obj":"Chemical"},{"id":"T146","span":{"begin":8751,"end":8757},"obj":"Chemical"},{"id":"T147","span":{"begin":8765,"end":8775},"obj":"Chemical"},{"id":"T148","span":{"begin":8911,"end":8913},"obj":"Chemical"},{"id":"T149","span":{"begin":8980,"end":8990},"obj":"Chemical"},{"id":"T150","span":{"begin":9035,"end":9042},"obj":"Chemical"},{"id":"T151","span":{"begin":9079,"end":9085},"obj":"Chemical"},{"id":"T152","span":{"begin":9318,"end":9321},"obj":"Chemical"},{"id":"T153","span":{"begin":9998,"end":10008},"obj":"Chemical"},{"id":"T154","span":{"begin":10042,"end":10057},"obj":"Chemical"},{"id":"T155","span":{"begin":10059,"end":10070},"obj":"Chemical"},{"id":"T156","span":{"begin":10076,"end":10090},"obj":"Chemical"},{"id":"T157","span":{"begin":10572,"end":10574},"obj":"Chemical"},{"id":"T159","span":{"begin":10595,"end":10597},"obj":"Chemical"},{"id":"T161","span":{"begin":10643,"end":10645},"obj":"Chemical"},{"id":"T163","span":{"begin":10730,"end":10732},"obj":"Chemical"},{"id":"T164","span":{"begin":11105,"end":11107},"obj":"Chemical"},{"id":"T166","span":{"begin":11224,"end":11226},"obj":"Chemical"},{"id":"T168","span":{"begin":11354,"end":11364},"obj":"Chemical"},{"id":"T169","span":{"begin":11440,"end":11447},"obj":"Chemical"},{"id":"T170","span":{"begin":11679,"end":11681},"obj":"Chemical"},{"id":"T172","span":{"begin":11696,"end":11698},"obj":"Chemical"},{"id":"T174","span":{"begin":11771,"end":11773},"obj":"Chemical"},{"id":"T176","span":{"begin":12003,"end":12006},"obj":"Chemical"},{"id":"T178","span":{"begin":12013,"end":12015},"obj":"Chemical"},{"id":"T180","span":{"begin":12650,"end":12659},"obj":"Chemical"},{"id":"T181","span":{"begin":12916,"end":12924},"obj":"Chemical"},{"id":"T184","span":{"begin":12926,"end":12935},"obj":"Chemical"},{"id":"T185","span":{"begin":12945,"end":12956},"obj":"Chemical"},{"id":"T186","span":{"begin":12951,"end":12956},"obj":"Chemical"},{"id":"T187","span":{"begin":12958,"end":12973},"obj":"Chemical"},{"id":"T188","span":{"begin":12986,"end":13000},"obj":"Chemical"},{"id":"T189","span":{"begin":13005,"end":13017},"obj":"Chemical"},{"id":"T190","span":{"begin":13028,"end":13036},"obj":"Chemical"},{"id":"T191","span":{"begin":13041,"end":13049},"obj":"Chemical"}],"attributes":[{"id":"A16","pred":"chebi_id","subj":"T16","obj":"http://purl.obolibrary.org/obo/CHEBI_33281"},{"id":"A17","pred":"chebi_id","subj":"T17","obj":"http://purl.obolibrary.org/obo/CHEBI_36080"},{"id":"A18","pred":"chebi_id","subj":"T18","obj":"http://purl.obolibrary.org/obo/CHEBI_25367"},{"id":"A19","pred":"chebi_id","subj":"T19","obj":"http://purl.obolibrary.org/obo/CHEBI_36080"},{"id":"A20","pred":"chebi_id","subj":"T20","obj":"http://purl.obolibrary.org/obo/CHEBI_82761"},{"id":"A21","pred":"chebi_id","subj":"T21","obj":"http://purl.obolibrary.org/obo/CHEBI_18059"},{"id":"A22","pred":"chebi_id","subj":"T22","obj":"http://purl.obolibrary.org/obo/CHEBI_36080"},{"id":"A23","pred":"chebi_id","subj":"T23","obj":"http://purl.obolibrary.org/obo/CHEBI_33385"},{"id":"A24","pred":"chebi_id","subj":"T24","obj":"http://purl.obolibrary.org/obo/CHEBI_59132"},{"id":"A25","pred":"chebi_id","subj":"T25","obj":"http://purl.obolibrary.org/obo/CHEBI_59132"},{"id":"A26","pred":"chebi_id","subj":"T26","obj":"http://purl.obolibrary.org/obo/CHEBI_59132"},{"id":"A27","pred":"chebi_id","subj":"T27","obj":"http://purl.obolibrary.org/obo/CHEBI_80551"},{"id":"A28","pred":"chebi_id","subj":"T28","obj":"http://purl.obolibrary.org/obo/CHEBI_80551"},{"id":"A29","pred":"chebi_id","subj":"T29","obj":"http://purl.obolibrary.org/obo/CHEBI_25367"},{"id":"A30","pred":"chebi_id","subj":"T30","obj":"http://purl.obolibrary.org/obo/CHEBI_74067"},{"id":"A31","pred":"chebi_id","subj":"T31","obj":"http://purl.obolibrary.org/obo/CHEBI_59132"},{"id":"A32","pred":"chebi_id","subj":"T32","obj":"http://purl.obolibrary.org/obo/CHEBI_59132"},{"id":"A33","pred":"chebi_id","subj":"T33","obj":"http://purl.obolibrary.org/obo/CHEBI_74067"},{"id":"A34","pred":"chebi_id","subj":"T34","obj":"http://purl.obolibrary.org/obo/CHEBI_59132"},{"id":"A35","pred":"chebi_id","subj":"T35","obj":"http://purl.obolibrary.org/obo/CHEBI_80551"},{"id":"A36","pred":"chebi_id","subj":"T36","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A37","pred":"chebi_id","subj":"T36","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A38","pred":"chebi_id","subj":"T38","obj":"http://purl.obolibrary.org/obo/CHEBI_33385"},{"id":"A39","pred":"chebi_id","subj":"T39","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A40","pred":"chebi_id","subj":"T39","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A41","pred":"chebi_id","subj":"T41","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A42","pred":"chebi_id","subj":"T41","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A43","pred":"chebi_id","subj":"T43","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A44","pred":"chebi_id","subj":"T43","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A45","pred":"chebi_id","subj":"T45","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A46","pred":"chebi_id","subj":"T45","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A47","pred":"chebi_id","subj":"T47","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A48","pred":"chebi_id","subj":"T47","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A49","pred":"chebi_id","subj":"T49","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A50","pred":"chebi_id","subj":"T49","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A51","pred":"chebi_id","subj":"T51","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A52","pred":"chebi_id","subj":"T51","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A53","pred":"chebi_id","subj":"T53","obj":"http://purl.obolibrary.org/obo/CHEBI_59132"},{"id":"A54","pred":"chebi_id","subj":"T54","obj":"http://purl.obolibrary.org/obo/CHEBI_36080"},{"id":"A55","pred":"chebi_id","subj":"T55","obj":"http://purl.obolibrary.org/obo/CHEBI_33252"},{"id":"A56","pred":"chebi_id","subj":"T56","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A57","pred":"chebi_id","subj":"T56","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A58","pred":"chebi_id","subj":"T58","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A59","pred":"chebi_id","subj":"T58","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A60","pred":"chebi_id","subj":"T60","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A61","pred":"chebi_id","subj":"T60","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A62","pred":"chebi_id","subj":"T62","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A63","pred":"chebi_id","subj":"T62","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A64","pred":"chebi_id","subj":"T64","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A65","pred":"chebi_id","subj":"T64","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A66","pred":"chebi_id","subj":"T66","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A67","pred":"chebi_id","subj":"T66","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A68","pred":"chebi_id","subj":"T68","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A69","pred":"chebi_id","subj":"T68","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A70","pred":"chebi_id","subj":"T70","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A71","pred":"chebi_id","subj":"T70","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A72","pred":"chebi_id","subj":"T72","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A73","pred":"chebi_id","subj":"T72","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A74","pred":"chebi_id","subj":"T74","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A75","pred":"chebi_id","subj":"T74","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A76","pred":"chebi_id","subj":"T76","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A77","pred":"chebi_id","subj":"T76","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A78","pred":"chebi_id","subj":"T78","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A79","pred":"chebi_id","subj":"T78","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A80","pred":"chebi_id","subj":"T80","obj":"http://purl.obolibrary.org/obo/CHEBI_138157"},{"id":"A81","pred":"chebi_id","subj":"T81","obj":"http://purl.obolibrary.org/obo/CHEBI_52214"},{"id":"A82","pred":"chebi_id","subj":"T82","obj":"http://purl.obolibrary.org/obo/CHEBI_52214"},{"id":"A83","pred":"chebi_id","subj":"T83","obj":"http://purl.obolibrary.org/obo/CHEBI_3478"},{"id":"A84","pred":"chebi_id","subj":"T84","obj":"http://purl.obolibrary.org/obo/CHEBI_16541"},{"id":"A85","pred":"chebi_id","subj":"T85","obj":"http://purl.obolibrary.org/obo/CHEBI_132592"},{"id":"A86","pred":"chebi_id","subj":"T85","obj":"http://purl.obolibrary.org/obo/CHEBI_50099"},{"id":"A87","pred":"chebi_id","subj":"T87","obj":"http://purl.obolibrary.org/obo/CHEBI_59132"},{"id":"A88","pred":"chebi_id","subj":"T88","obj":"http://purl.obolibrary.org/obo/CHEBI_141424"},{"id":"A89","pred":"chebi_id","subj":"T88","obj":"http://purl.obolibrary.org/obo/CHEBI_25573"},{"id":"A90","pred":"chebi_id","subj":"T88","obj":"http://purl.obolibrary.org/obo/CHEBI_1224"},{"id":"A91","pred":"chebi_id","subj":"T91","obj":"http://purl.obolibrary.org/obo/CHEBI_141424"},{"id":"A92","pred":"chebi_id","subj":"T91","obj":"http://purl.obolibrary.org/obo/CHEBI_25573"},{"id":"A93","pred":"chebi_id","subj":"T91","obj":"http://purl.obolibrary.org/obo/CHEBI_1224"},{"id":"A94","pred":"chebi_id","subj":"T94","obj":"http://purl.obolibrary.org/obo/CHEBI_25367"},{"id":"A95","pred":"chebi_id","subj":"T95","obj":"http://purl.obolibrary.org/obo/CHEBI_52998"},{"id":"A96","pred":"chebi_id","subj":"T96","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A97","pred":"chebi_id","subj":"T96","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A98","pred":"chebi_id","subj":"T98","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A99","pred":"chebi_id","subj":"T98","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A100","pred":"chebi_id","subj":"T100","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A101","pred":"chebi_id","subj":"T100","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A102","pred":"chebi_id","subj":"T102","obj":"http://purl.obolibrary.org/obo/CHEBI_16991"},{"id":"A103","pred":"chebi_id","subj":"T103","obj":"http://purl.obolibrary.org/obo/CHEBI_67208"},{"id":"A104","pred":"chebi_id","subj":"T104","obj":"http://purl.obolibrary.org/obo/CHEBI_17089"},{"id":"A105","pred":"chebi_id","subj":"T105","obj":"http://purl.obolibrary.org/obo/CHEBI_141424"},{"id":"A106","pred":"chebi_id","subj":"T105","obj":"http://purl.obolibrary.org/obo/CHEBI_25573"},{"id":"A107","pred":"chebi_id","subj":"T105","obj":"http://purl.obolibrary.org/obo/CHEBI_1224"},{"id":"A108","pred":"chebi_id","subj":"T108","obj":"http://purl.obolibrary.org/obo/CHEBI_36976"},{"id":"A109","pred":"chebi_id","subj":"T109","obj":"http://purl.obolibrary.org/obo/CHEBI_36080"},{"id":"A110","pred":"chebi_id","subj":"T110","obj":"http://purl.obolibrary.org/obo/CHEBI_36080"},{"id":"A111","pred":"chebi_id","subj":"T111","obj":"http://purl.obolibrary.org/obo/CHEBI_22587"},{"id":"A112","pred":"chebi_id","subj":"T112","obj":"http://purl.obolibrary.org/obo/CHEBI_22587"},{"id":"A113","pred":"chebi_id","subj":"T113","obj":"http://purl.obolibrary.org/obo/CHEBI_52999"},{"id":"A114","pred":"chebi_id","subj":"T114","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A115","pred":"chebi_id","subj":"T114","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A116","pred":"chebi_id","subj":"T116","obj":"http://purl.obolibrary.org/obo/CHEBI_141424"},{"id":"A117","pred":"chebi_id","subj":"T116","obj":"http://purl.obolibrary.org/obo/CHEBI_25573"},{"id":"A118","pred":"chebi_id","subj":"T116","obj":"http://purl.obolibrary.org/obo/CHEBI_1224"},{"id":"A119","pred":"chebi_id","subj":"T119","obj":"http://purl.obolibrary.org/obo/CHEBI_33385"},{"id":"A120","pred":"chebi_id","subj":"T120","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A121","pred":"chebi_id","subj":"T120","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A122","pred":"chebi_id","subj":"T122","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A123","pred":"chebi_id","subj":"T122","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A124","pred":"chebi_id","subj":"T124","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A125","pred":"chebi_id","subj":"T124","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A126","pred":"chebi_id","subj":"T126","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A127","pred":"chebi_id","subj":"T126","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A128","pred":"chebi_id","subj":"T128","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A129","pred":"chebi_id","subj":"T128","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A130","pred":"chebi_id","subj":"T130","obj":"http://purl.obolibrary.org/obo/CHEBI_24433"},{"id":"A131","pred":"chebi_id","subj":"T131","obj":"http://purl.obolibrary.org/obo/CHEBI_36080"},{"id":"A132","pred":"chebi_id","subj":"T132","obj":"http://purl.obolibrary.org/obo/CHEBI_2719"},{"id":"A133","pred":"chebi_id","subj":"T133","obj":"http://purl.obolibrary.org/obo/CHEBI_36080"},{"id":"A134","pred":"chebi_id","subj":"T134","obj":"http://purl.obolibrary.org/obo/CHEBI_74067"},{"id":"A135","pred":"chebi_id","subj":"T135","obj":"http://purl.obolibrary.org/obo/CHEBI_33709"},{"id":"A136","pred":"chebi_id","subj":"T136","obj":"http://purl.obolibrary.org/obo/CHEBI_46882"},{"id":"A137","pred":"chebi_id","subj":"T137","obj":"http://purl.obolibrary.org/obo/CHEBI_37527"},{"id":"A138","pred":"chebi_id","subj":"T138","obj":"http://purl.obolibrary.org/obo/CHEBI_36080"},{"id":"A139","pred":"chebi_id","subj":"T139","obj":"http://purl.obolibrary.org/obo/CHEBI_141424"},{"id":"A140","pred":"chebi_id","subj":"T139","obj":"http://purl.obolibrary.org/obo/CHEBI_25573"},{"id":"A141","pred":"chebi_id","subj":"T139","obj":"http://purl.obolibrary.org/obo/CHEBI_1224"},{"id":"A142","pred":"chebi_id","subj":"T142","obj":"http://purl.obolibrary.org/obo/CHEBI_22587"},{"id":"A143","pred":"chebi_id","subj":"T143","obj":"http://purl.obolibrary.org/obo/CHEBI_16467"},{"id":"A144","pred":"chebi_id","subj":"T143","obj":"http://purl.obolibrary.org/obo/CHEBI_29952"},{"id":"A145","pred":"chebi_id","subj":"T145","obj":"http://purl.obolibrary.org/obo/CHEBI_3165"},{"id":"A146","pred":"chebi_id","subj":"T146","obj":"http://purl.obolibrary.org/obo/CHEBI_52214"},{"id":"A147","pred":"chebi_id","subj":"T147","obj":"http://purl.obolibrary.org/obo/CHEBI_3165"},{"id":"A148","pred":"chebi_id","subj":"T148","obj":"http://purl.obolibrary.org/obo/CHEBI_51707"},{"id":"A149","pred":"chebi_id","subj":"T149","obj":"http://purl.obolibrary.org/obo/CHEBI_3165"},{"id":"A150","pred":"chebi_id","subj":"T150","obj":"http://purl.obolibrary.org/obo/CHEBI_36080"},{"id":"A151","pred":"chebi_id","subj":"T151","obj":"http://purl.obolibrary.org/obo/CHEBI_17822"},{"id":"A152","pred":"chebi_id","subj":"T152","obj":"http://purl.obolibrary.org/obo/CHEBI_63620"},{"id":"A153","pred":"chebi_id","subj":"T153","obj":"http://purl.obolibrary.org/obo/CHEBI_3165"},{"id":"A154","pred":"chebi_id","subj":"T154","obj":"http://purl.obolibrary.org/obo/CHEBI_50858"},{"id":"A155","pred":"chebi_id","subj":"T155","obj":"http://purl.obolibrary.org/obo/CHEBI_28918"},{"id":"A156","pred":"chebi_id","subj":"T156","obj":"http://purl.obolibrary.org/obo/CHEBI_37956"},{"id":"A157","pred":"chebi_id","subj":"T157","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A158","pred":"chebi_id","subj":"T157","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A159","pred":"chebi_id","subj":"T159","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A160","pred":"chebi_id","subj":"T159","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A161","pred":"chebi_id","subj":"T161","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A162","pred":"chebi_id","subj":"T161","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A163","pred":"chebi_id","subj":"T163","obj":"http://purl.obolibrary.org/obo/CHEBI_73924"},{"id":"A164","pred":"chebi_id","subj":"T164","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A165","pred":"chebi_id","subj":"T164","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A166","pred":"chebi_id","subj":"T166","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A167","pred":"chebi_id","subj":"T166","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A168","pred":"chebi_id","subj":"T168","obj":"http://purl.obolibrary.org/obo/CHEBI_36976"},{"id":"A169","pred":"chebi_id","subj":"T169","obj":"http://purl.obolibrary.org/obo/CHEBI_36080"},{"id":"A170","pred":"chebi_id","subj":"T170","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A171","pred":"chebi_id","subj":"T170","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A172","pred":"chebi_id","subj":"T172","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A173","pred":"chebi_id","subj":"T172","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A174","pred":"chebi_id","subj":"T174","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A175","pred":"chebi_id","subj":"T174","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A176","pred":"chebi_id","subj":"T176","obj":"http://purl.obolibrary.org/obo/CHEBI_132592"},{"id":"A177","pred":"chebi_id","subj":"T176","obj":"http://purl.obolibrary.org/obo/CHEBI_50099"},{"id":"A178","pred":"chebi_id","subj":"T178","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A179","pred":"chebi_id","subj":"T178","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A180","pred":"chebi_id","subj":"T180","obj":"http://purl.obolibrary.org/obo/CHEBI_33284"},{"id":"A181","pred":"chebi_id","subj":"T181","obj":"http://purl.obolibrary.org/obo/CHEBI_16467"},{"id":"A182","pred":"chebi_id","subj":"T181","obj":"http://purl.obolibrary.org/obo/CHEBI_29016"},{"id":"A183","pred":"chebi_id","subj":"T181","obj":"http://purl.obolibrary.org/obo/CHEBI_32696"},{"id":"A184","pred":"chebi_id","subj":"T184","obj":"http://purl.obolibrary.org/obo/CHEBI_28300"},{"id":"A185","pred":"chebi_id","subj":"T185","obj":"http://purl.obolibrary.org/obo/CHEBI_35366"},{"id":"A186","pred":"chebi_id","subj":"T186","obj":"http://purl.obolibrary.org/obo/CHEBI_37527"},{"id":"A187","pred":"chebi_id","subj":"T187","obj":"http://purl.obolibrary.org/obo/CHEBI_26561"},{"id":"A188","pred":"chebi_id","subj":"T188","obj":"http://purl.obolibrary.org/obo/CHEBI_27027"},{"id":"A189","pred":"chebi_id","subj":"T189","obj":"http://purl.obolibrary.org/obo/CHEBI_22586"},{"id":"A190","pred":"chebi_id","subj":"T190","obj":"http://purl.obolibrary.org/obo/CHEBI_33229"},{"id":"A191","pred":"chebi_id","subj":"T191","obj":"http://purl.obolibrary.org/obo/CHEBI_46662"}],"text":"Immune system, inflammation and COVID-19\nThe immune system protects the human body from infections by a series of pathogen (bacteria, viruses, fungi, parasites) [5]. A self-tolerance system prevents the immune response from damaging human tissues. The immune system is always active, carrying out surveillance. The defense to first exposure to the pathogen is represented by two complementary and cooperating functional divisions, the innate immune and, on the other hand, the adaptive immune response, that represents a response based on previous exposure [6]. The innate immune system is represented by dendritic cells, macrophages and neutrophils, with phagocytic activity, and by eosinophils, mast cells and natural killer cells, which release specific soluble antimicrobial factors. The innate immune system includes physical barriers, represented by interconnected epithelial cells (e.g. tight junctions and cellular interactions mediated by cadherin), epithelial cilia and the mucus layer of the respiratory, gastrointestinal and genitourinary epithelium. Moreover, soluble proteins and small bioactive molecules such as complement proteins, defensins and ficolins 1-3, pro-inflammatory cytokines, chemokines, lipid mediators of inflammation, membrane-bound receptors and cytoplasmic proteins are part of the innate immune system. Both innate and adaptive immunity is mediated by leukocytes. Lymphocytes circulate between the blood system and the lymphatic system, passing through the peripheral lymphoid organs, which includes the spleen, tonsils, appendix, lymph nodes and gut-associated lymphoid tissue (GALT). From a common lymphoid progenitor, four major populations of mature lymphocytes are derived, that belong to the adaptive immune system: of B lymphocytes (B cells) and T lymphocytes (T cells), natural killer (NK) cells, and NK-T cells. T-cells can be further categorized to cytotoxic T-cells (TC cells), helper T-cells (Th) and suppressor T-cells. The specific antigenic receptors of the adaptive response are represented by genes that code for an intact T cell receptor (TCR) and immunoglobulin genes (B cell antigen receptor; Ig). TCR is capable of binding the antigen processed by antigen-presenting cells (APC). Dendritic cells represent the most powerful class of APC, and express molecules of the major histocompatibility complex (MHC) of class I and II, necessary for the recognition of the antigen processed by TCR on T cells [7].\nFollowing the presentation of viral antigens via MHC II, the T helper CD4+ lymphocytes are activated and switch to the T helper 1 phenotype [8].\nThe activated T helper lymphocytes proliferate and release cytokines: after stimulation by antigen and APC, the Th0 cells begin to produce interleukin (IL)-2. Meanwhile, Th cells differentiate into Th1, Th2 and Th17 according to the nature of the cytokines present in the activation site: IL-12 produced by macrophages and type I Interferon (IFN) or NK cells induce differentiation towards Th1, IL-4 produced by NK1.1 + T cells, basophils or mast cells induce differentiation towards Th2, and IL-1b, IL-23, TGFβ and IL-6 induce differentiation towards Th17 [9]. Th17 cells produce IL-17 and IL-22, and antigen-induced Treg (iTreg).\nThe binding of the cytokine to its transmembrane cell surface receptor activates an intracellular signal transduction pathway, generally a Janus kinase (Jak), which, via a kinase cascade, phosphorylates its transcription protein (STAT). Phosphorylated STAT dimers and moves to the nucleus, initiating a new gene transcription. Mutation of STAT1 increases susceptibility to virus infections because it is involved in various signalling pathways, including IFN-α/β, IFN- γ, IFN-l, IL-2, IL-3, IL-6, IL-9, IL-10, IL-11, IL-12, IL-15, IL-21, IL-22, IL-26 and IL-27 [10], and chemokines of several types such as C-X-C motif chemokine ligand 10 (CXCL-10), Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted (RANTES)/Chemokine (C–C motif) ligand 5 (CCL-5), Monocyte Chemoattractant Protein-1 (MCP-1) [11]. IFN-γ promotes antigen-specific antibody production, increasing the activity of phagocytosis. In the meantime, PRRs trigger inflammatory signalling, with activation of transcription factors like nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). NFκB is the key transcriptional regulator of many pro-inflammatory cytokines, adhesion molecules, chemokines, growth factors and other mediators of inflammation, as tumour necrosis factor (TNF), interleukins 1 (IL-1β), 6 (IL-6), and 12 (IL-12), promotes cellular proliferation and protects against apoptosis providing a mechanism that determines chronic inflammation. The recognition of pathogens is achieved through the presence of pattern recognition receptors (PRRs) [12]. PRRs identify the microbe-associated molecular patterns (MAMPs), and defensive responses is activated. PRRs include Toll-like receptors (TLRs), that are able to recognize viral DNA, viral double-stranded RNA and viral single-stranded RNA. TLRs are expressed on macrophages, dendritic cells, neutrophils, eosinophils, epithelial cells and keratinocytes. In particular, intracellular TLR-7 and TLR-8 allow the innate recognition of the single-stranded RNA of coronaviruses [13]. Intracellular and extracellular PRRs recognized spike glycoprotein, of the coronavirus coat, starting the inflammatory process, through the NFκB pathway [14]. Moreover, Nucleotide-Binding Domain, Leucine-Rich Repeat (NLR) proteins have also been identified, and NALP3 (NACHT, LRR and PYD domains-containing protein 3) has a special function in the innate immune response [15]. The processes involved in antiviral immunity is shown in Fig. 1.\nFig. 1 Graphical representation of antiviral SARS-Coronavirus 2 immunity. B: B lymphocyte; CTL: cytotoxic; T lymphocyte; IFN: interferon; Ig: immunoglobulin; IL: interleukin; MHC: major histocompatibility class; NFκB: nuclear factor kappa-light- chain- enhancer of activated B cells; NK: natural killer cell; Th: helper T lymphocyte; TLR: Toll-like receptor; TNF: tumour necrosis factor\nNormal inflammation is self-limiting because the production of pro-inflammatory cytokines (Th1 cytokines) is followed almost immediately by the production of anti-inflammatory cytokines (Th2 cytokines; IL-1, IL-10, IL-13, etc.). Chronic inflammation seems to result when the initiating factors persist, or there is some sort of failure of the resolution process.\nDysfunction of the immune system and the loss of homeostatic equilibrium between TREG cells (IL- 10) and Th17 cells (IL-17) was observed in different pathological situations [16], and it is believed to increase the risk of viral infections, including SARS- coronavirus 2 (SARS-CoV-2) [14].\nSARS-CoV-2 is an enveloped positive-strand RNA virus in the family Coronaviridae, group 2b, which encodes the viral replicase and four structural proteins: spike (S), envelope (E) and membrane (M), present in the viral envelope, and nucleocapsid (N) [17].\nThe access route of SARS-CoV-2 is represented by a hydrophobic pocket of the extracellular catalytic domain of Angiotensin-converting enzyme 2 (ACE2) [18]. SARS-CoV peak S protein trimers bind ACE2, expressed in endothelial cells of the vasculature and in the epithelia of the lungs, intestine, heart, brain and kidney. SARS-CoV-2 enters the cell for endocytosis and membrane fusion. Once the virus has infected the cell, it follows a downregulation of ACE2 with a consequent local increase in the levels of Ang II, and the development of acute respiratory distress syndrome (ARDS) [19]. The role of ACE2 in the gut, for expression of neutral amino acid transporters, could explain diarrhoea and intestinal inflammation observed in COVID-19. Moreover, SARS-CoV2 protein E activates the NFκB inflammatory pathway with the consequent activation of MAPK p38, resulting in exacerbation of inflammation and immunopathology [20]. Following the SARS-CoV-2 infection, in the incubation stage and in the non-serious form of COVID-19, the immune system activates the specific adaptive immune response to eliminate the virus, which should be sufficient to block viral propagation and disease progression. The antiviral system functions well in the presence of general good health and an adequate genetic background. However, the presence of concomitant pathologies (obesity, cardiovascular diseases, diabetes, neurodegenerative diseases and cancer), malnutrition, and impaired immune response determine the spread of the virus and a massive destruction of the affected tissues, especially in organs that have high ACE2 expression [21]. As noted earlier, SARS-CoV-2 enters the cell via ACE2; that inactivates des-Arg bradykinin, which is a potent ligand of the bradykinin receptor type 1 (BDKRB1).This receptor, localized on endothelial cells, is up-regulated by inflammatory cytokines, which is unlike the B2 receptor, that is constituently expressed and is the receptor for bradykinin (BDK). BDK is produced from an inactive pre-protein kininogen through activation by the serine protease kallikrein; in addition, it is considered a potent regulator of blood pressure [22], because it induces vasodilation, natriuresis, and hypotension upon activation of the BDKRB2 receptor. BDK is strongly integrated with the RAS, and the BDK receptor signaling is increased by angiotensin’s action [23].\nInterestingly, ACE has a higher affinity for BDK [24] and therefore in conditions where ACE is low, the vasopressor system is moved toward a BDK-directed hypotensive axis. BDK takes part in the inflammatory response after injury and acts to induce pain via stimulation of the BDKRB1 receptor, which also causes neutrophil recruitment and a major vascular permeability [25, 26].\nDuring the infection, as long as the virus persists, there is dysfunction of ACE2 function, leading to the dysregulation of the kinin-kallikrein pathway and thus causing the angioedema [27]. Some evidence that the edema is bradykinin-generated includes resistance to corticosteroids, epinephrine, and antihistamines in the management of reducing the pulmonary edema in COVID-19 patients. In fact, the so called Bradykinin Storm is likely responsible for most of the observed COVID-19 symptoms.\nInflammation plays a fundamental role in the pathogenesis and progression of COVID-19, ranging from common colds to fatal cases of pneumonia due to the cytokine release syndrome (CRS) that affected patients, determining the severe conditions. In COVID-19 the homeostatic equilibrium between TREG cells (IL-10) and Th17 cells (IL-17) is broken: inflammatory cytokine levels (IL-1, TNF) are elevated in the lungs of COVID-19 patients, resulting in an increase in HA-synthase-2 (HAS2) in alveolar epithelial cells CD31+, EpCAM+ and fibroblasts. The imbalance between pro-inflammatory and anti-inflammatory cytokines, leads to the CRS, an excessive and damaging host inflammation [28]. As a consequence of CRS [29], due to a severe infection of SARS-CoV-2 of the respiratory epithelium, the ARDS was observed in COVID-19 [30]. Edema and an IL-1β mediated proinflammatory response were increased in the lung parenchyma. Macrophages and dendritic cells produce IL-1β through macro-molecular complexes called inflammasomes, including the major element present in the pulmonary tissue and the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome [20]. Following a precise stimulus, the activation and recruitment domain of caspase (ASC) and the catalytically inactive procaspase-1 assemble, the procaspase-1 turns into active caspase-1, the inactive pro-IL-1β matures in IL-1β and the NLRP3 inflammasome is activated. The NLRP3 inflammasomes and IL-1β driven proinflammatory cascades correlate with worsening of several respiratory diseases, including COVID-19.\nPatients affected by obesity showed a severe consequence of COVID-19 [31], due to the high concentrations of TNF-α, MCP-1 and IL-6 produced in the meantime by visceral and subcutaneous adipose tissue and by innate immunity [32]. Moreover, leptin, released by adipose tissue, helps to increase inflammatory milieu with a dysregulation of the immune response [33].\nThis umbrella review seeks to answer the question of whether a nutritional approach can be used to enhance the immune system’s response to obesity in obese patients affected by COVID-19.\nImmunonutrition has been based on the concept that malnutrition impairs immune function, used to modify inflammatory or immune responses. This concept may be applied to any situation in which a supply of specific nutrients is necessary to modify inflammatory or immune responses. Immunonutrients can promote patient recovery by inhibiting inflammatory responses and regulating immune function. Therefore, immunonutrition involves feeding enriched with various pharmaconutrients (arginine, glutamine, omega-3-fatty acids, ribonucleotides and certain trace elements and antioxidants compound, vitamins and minerals) to modulate inflammatory responses, the acquired immune response, and to improve patient outcomes [34].\nPersonalized immunonutrition for patients with obesity should be the first therapeutic choice to reduce the risk of infections and the disease course in COVID-19 patients. That therapeutic strategy could be effective in case of other potential epidemic infections. It would also allow a reduction of the enormous medical care cost supported by the National Health Service."}

{"project":"LitCovid-PD-HP","denotations":[{"id":"T8","span":{"begin":4490,"end":4496},"obj":"Phenotype"},{"id":"T9","span":{"begin":6084,"end":6090},"obj":"Phenotype"},{"id":"T10","span":{"begin":7561,"end":7581},"obj":"Phenotype"},{"id":"T11","span":{"begin":7698,"end":7707},"obj":"Phenotype"},{"id":"T12","span":{"begin":8371,"end":8378},"obj":"Phenotype"},{"id":"T13","span":{"begin":8380,"end":8403},"obj":"Phenotype"},{"id":"T14","span":{"begin":8415,"end":8441},"obj":"Phenotype"},{"id":"T15","span":{"begin":8446,"end":8452},"obj":"Phenotype"},{"id":"T16","span":{"begin":8455,"end":8467},"obj":"Phenotype"},{"id":"T17","span":{"begin":9230,"end":9241},"obj":"Phenotype"},{"id":"T18","span":{"begin":9645,"end":9649},"obj":"Phenotype"},{"id":"T19","span":{"begin":9949,"end":9959},"obj":"Phenotype"},{"id":"T20","span":{"begin":9989,"end":9994},"obj":"Phenotype"},{"id":"T21","span":{"begin":10125,"end":10140},"obj":"Phenotype"},{"id":"T22","span":{"begin":10400,"end":10409},"obj":"Phenotype"},{"id":"T23","span":{"begin":10421,"end":10446},"obj":"Phenotype"},{"id":"T24","span":{"begin":10990,"end":11006},"obj":"Phenotype"},{"id":"T25","span":{"begin":11092,"end":11097},"obj":"Phenotype"},{"id":"T26","span":{"begin":11908,"end":11915},"obj":"Phenotype"},{"id":"T27","span":{"begin":12389,"end":12396},"obj":"Phenotype"},{"id":"T28","span":{"begin":12488,"end":12500},"obj":"Phenotype"},{"id":"T29","span":{"begin":13202,"end":13209},"obj":"Phenotype"}],"attributes":[{"id":"A8","pred":"hp_id","subj":"T8","obj":"http://purl.obolibrary.org/obo/HP_0002664"},{"id":"A9","pred":"hp_id","subj":"T9","obj":"http://purl.obolibrary.org/obo/HP_0002664"},{"id":"A10","pred":"hp_id","subj":"T10","obj":"http://purl.obolibrary.org/obo/HP_0002098"},{"id":"A11","pred":"hp_id","subj":"T11","obj":"http://purl.obolibrary.org/obo/HP_0002014"},{"id":"A12","pred":"hp_id","subj":"T12","obj":"http://purl.obolibrary.org/obo/HP_0001513"},{"id":"A13","pred":"hp_id","subj":"T13","obj":"http://purl.obolibrary.org/obo/HP_0001626"},{"id":"A14","pred":"hp_id","subj":"T14","obj":"http://purl.obolibrary.org/obo/HP_0002180"},{"id":"A15","pred":"hp_id","subj":"T15","obj":"http://purl.obolibrary.org/obo/HP_0002664"},{"id":"A16","pred":"hp_id","subj":"T16","obj":"http://purl.obolibrary.org/obo/HP_0004395"},{"id":"A17","pred":"hp_id","subj":"T17","obj":"http://purl.obolibrary.org/obo/HP_0002615"},{"id":"A18","pred":"hp_id","subj":"T18","obj":"http://purl.obolibrary.org/obo/HP_0012531"},{"id":"A19","pred":"hp_id","subj":"T19","obj":"http://purl.obolibrary.org/obo/HP_0100665"},{"id":"A20","pred":"hp_id","subj":"T20","obj":"http://purl.obolibrary.org/obo/HP_0000969"},{"id":"A21","pred":"hp_id","subj":"T21","obj":"http://purl.obolibrary.org/obo/HP_0100598"},{"id":"A22","pred":"hp_id","subj":"T22","obj":"http://purl.obolibrary.org/obo/HP_0002090"},{"id":"A23","pred":"hp_id","subj":"T23","obj":"http://purl.obolibrary.org/obo/HP_0033041"},{"id":"A24","pred":"hp_id","subj":"T24","obj":"http://purl.obolibrary.org/obo/HP_0032169"},{"id":"A25","pred":"hp_id","subj":"T25","obj":"http://purl.obolibrary.org/obo/HP_0000969"},{"id":"A26","pred":"hp_id","subj":"T26","obj":"http://purl.obolibrary.org/obo/HP_0001513"},{"id":"A27","pred":"hp_id","subj":"T27","obj":"http://purl.obolibrary.org/obo/HP_0001513"},{"id":"A28","pred":"hp_id","subj":"T28","obj":"http://purl.obolibrary.org/obo/HP_0004395"},{"id":"A29","pred":"hp_id","subj":"T29","obj":"http://purl.obolibrary.org/obo/HP_0001513"}],"text":"Immune system, inflammation and COVID-19\nThe immune system protects the human body from infections by a series of pathogen (bacteria, viruses, fungi, parasites) [5]. A self-tolerance system prevents the immune response from damaging human tissues. The immune system is always active, carrying out surveillance. The defense to first exposure to the pathogen is represented by two complementary and cooperating functional divisions, the innate immune and, on the other hand, the adaptive immune response, that represents a response based on previous exposure [6]. The innate immune system is represented by dendritic cells, macrophages and neutrophils, with phagocytic activity, and by eosinophils, mast cells and natural killer cells, which release specific soluble antimicrobial factors. The innate immune system includes physical barriers, represented by interconnected epithelial cells (e.g. tight junctions and cellular interactions mediated by cadherin), epithelial cilia and the mucus layer of the respiratory, gastrointestinal and genitourinary epithelium. Moreover, soluble proteins and small bioactive molecules such as complement proteins, defensins and ficolins 1-3, pro-inflammatory cytokines, chemokines, lipid mediators of inflammation, membrane-bound receptors and cytoplasmic proteins are part of the innate immune system. Both innate and adaptive immunity is mediated by leukocytes. Lymphocytes circulate between the blood system and the lymphatic system, passing through the peripheral lymphoid organs, which includes the spleen, tonsils, appendix, lymph nodes and gut-associated lymphoid tissue (GALT). From a common lymphoid progenitor, four major populations of mature lymphocytes are derived, that belong to the adaptive immune system: of B lymphocytes (B cells) and T lymphocytes (T cells), natural killer (NK) cells, and NK-T cells. T-cells can be further categorized to cytotoxic T-cells (TC cells), helper T-cells (Th) and suppressor T-cells. The specific antigenic receptors of the adaptive response are represented by genes that code for an intact T cell receptor (TCR) and immunoglobulin genes (B cell antigen receptor; Ig). TCR is capable of binding the antigen processed by antigen-presenting cells (APC). Dendritic cells represent the most powerful class of APC, and express molecules of the major histocompatibility complex (MHC) of class I and II, necessary for the recognition of the antigen processed by TCR on T cells [7].\nFollowing the presentation of viral antigens via MHC II, the T helper CD4+ lymphocytes are activated and switch to the T helper 1 phenotype [8].\nThe activated T helper lymphocytes proliferate and release cytokines: after stimulation by antigen and APC, the Th0 cells begin to produce interleukin (IL)-2. Meanwhile, Th cells differentiate into Th1, Th2 and Th17 according to the nature of the cytokines present in the activation site: IL-12 produced by macrophages and type I Interferon (IFN) or NK cells induce differentiation towards Th1, IL-4 produced by NK1.1 + T cells, basophils or mast cells induce differentiation towards Th2, and IL-1b, IL-23, TGFβ and IL-6 induce differentiation towards Th17 [9]. Th17 cells produce IL-17 and IL-22, and antigen-induced Treg (iTreg).\nThe binding of the cytokine to its transmembrane cell surface receptor activates an intracellular signal transduction pathway, generally a Janus kinase (Jak), which, via a kinase cascade, phosphorylates its transcription protein (STAT). Phosphorylated STAT dimers and moves to the nucleus, initiating a new gene transcription. Mutation of STAT1 increases susceptibility to virus infections because it is involved in various signalling pathways, including IFN-α/β, IFN- γ, IFN-l, IL-2, IL-3, IL-6, IL-9, IL-10, IL-11, IL-12, IL-15, IL-21, IL-22, IL-26 and IL-27 [10], and chemokines of several types such as C-X-C motif chemokine ligand 10 (CXCL-10), Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted (RANTES)/Chemokine (C–C motif) ligand 5 (CCL-5), Monocyte Chemoattractant Protein-1 (MCP-1) [11]. IFN-γ promotes antigen-specific antibody production, increasing the activity of phagocytosis. In the meantime, PRRs trigger inflammatory signalling, with activation of transcription factors like nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). NFκB is the key transcriptional regulator of many pro-inflammatory cytokines, adhesion molecules, chemokines, growth factors and other mediators of inflammation, as tumour necrosis factor (TNF), interleukins 1 (IL-1β), 6 (IL-6), and 12 (IL-12), promotes cellular proliferation and protects against apoptosis providing a mechanism that determines chronic inflammation. The recognition of pathogens is achieved through the presence of pattern recognition receptors (PRRs) [12]. PRRs identify the microbe-associated molecular patterns (MAMPs), and defensive responses is activated. PRRs include Toll-like receptors (TLRs), that are able to recognize viral DNA, viral double-stranded RNA and viral single-stranded RNA. TLRs are expressed on macrophages, dendritic cells, neutrophils, eosinophils, epithelial cells and keratinocytes. In particular, intracellular TLR-7 and TLR-8 allow the innate recognition of the single-stranded RNA of coronaviruses [13]. Intracellular and extracellular PRRs recognized spike glycoprotein, of the coronavirus coat, starting the inflammatory process, through the NFκB pathway [14]. Moreover, Nucleotide-Binding Domain, Leucine-Rich Repeat (NLR) proteins have also been identified, and NALP3 (NACHT, LRR and PYD domains-containing protein 3) has a special function in the innate immune response [15]. The processes involved in antiviral immunity is shown in Fig. 1.\nFig. 1 Graphical representation of antiviral SARS-Coronavirus 2 immunity. B: B lymphocyte; CTL: cytotoxic; T lymphocyte; IFN: interferon; Ig: immunoglobulin; IL: interleukin; MHC: major histocompatibility class; NFκB: nuclear factor kappa-light- chain- enhancer of activated B cells; NK: natural killer cell; Th: helper T lymphocyte; TLR: Toll-like receptor; TNF: tumour necrosis factor\nNormal inflammation is self-limiting because the production of pro-inflammatory cytokines (Th1 cytokines) is followed almost immediately by the production of anti-inflammatory cytokines (Th2 cytokines; IL-1, IL-10, IL-13, etc.). Chronic inflammation seems to result when the initiating factors persist, or there is some sort of failure of the resolution process.\nDysfunction of the immune system and the loss of homeostatic equilibrium between TREG cells (IL- 10) and Th17 cells (IL-17) was observed in different pathological situations [16], and it is believed to increase the risk of viral infections, including SARS- coronavirus 2 (SARS-CoV-2) [14].\nSARS-CoV-2 is an enveloped positive-strand RNA virus in the family Coronaviridae, group 2b, which encodes the viral replicase and four structural proteins: spike (S), envelope (E) and membrane (M), present in the viral envelope, and nucleocapsid (N) [17].\nThe access route of SARS-CoV-2 is represented by a hydrophobic pocket of the extracellular catalytic domain of Angiotensin-converting enzyme 2 (ACE2) [18]. SARS-CoV peak S protein trimers bind ACE2, expressed in endothelial cells of the vasculature and in the epithelia of the lungs, intestine, heart, brain and kidney. SARS-CoV-2 enters the cell for endocytosis and membrane fusion. Once the virus has infected the cell, it follows a downregulation of ACE2 with a consequent local increase in the levels of Ang II, and the development of acute respiratory distress syndrome (ARDS) [19]. The role of ACE2 in the gut, for expression of neutral amino acid transporters, could explain diarrhoea and intestinal inflammation observed in COVID-19. Moreover, SARS-CoV2 protein E activates the NFκB inflammatory pathway with the consequent activation of MAPK p38, resulting in exacerbation of inflammation and immunopathology [20]. Following the SARS-CoV-2 infection, in the incubation stage and in the non-serious form of COVID-19, the immune system activates the specific adaptive immune response to eliminate the virus, which should be sufficient to block viral propagation and disease progression. The antiviral system functions well in the presence of general good health and an adequate genetic background. However, the presence of concomitant pathologies (obesity, cardiovascular diseases, diabetes, neurodegenerative diseases and cancer), malnutrition, and impaired immune response determine the spread of the virus and a massive destruction of the affected tissues, especially in organs that have high ACE2 expression [21]. As noted earlier, SARS-CoV-2 enters the cell via ACE2; that inactivates des-Arg bradykinin, which is a potent ligand of the bradykinin receptor type 1 (BDKRB1).This receptor, localized on endothelial cells, is up-regulated by inflammatory cytokines, which is unlike the B2 receptor, that is constituently expressed and is the receptor for bradykinin (BDK). BDK is produced from an inactive pre-protein kininogen through activation by the serine protease kallikrein; in addition, it is considered a potent regulator of blood pressure [22], because it induces vasodilation, natriuresis, and hypotension upon activation of the BDKRB2 receptor. BDK is strongly integrated with the RAS, and the BDK receptor signaling is increased by angiotensin’s action [23].\nInterestingly, ACE has a higher affinity for BDK [24] and therefore in conditions where ACE is low, the vasopressor system is moved toward a BDK-directed hypotensive axis. BDK takes part in the inflammatory response after injury and acts to induce pain via stimulation of the BDKRB1 receptor, which also causes neutrophil recruitment and a major vascular permeability [25, 26].\nDuring the infection, as long as the virus persists, there is dysfunction of ACE2 function, leading to the dysregulation of the kinin-kallikrein pathway and thus causing the angioedema [27]. Some evidence that the edema is bradykinin-generated includes resistance to corticosteroids, epinephrine, and antihistamines in the management of reducing the pulmonary edema in COVID-19 patients. In fact, the so called Bradykinin Storm is likely responsible for most of the observed COVID-19 symptoms.\nInflammation plays a fundamental role in the pathogenesis and progression of COVID-19, ranging from common colds to fatal cases of pneumonia due to the cytokine release syndrome (CRS) that affected patients, determining the severe conditions. In COVID-19 the homeostatic equilibrium between TREG cells (IL-10) and Th17 cells (IL-17) is broken: inflammatory cytokine levels (IL-1, TNF) are elevated in the lungs of COVID-19 patients, resulting in an increase in HA-synthase-2 (HAS2) in alveolar epithelial cells CD31+, EpCAM+ and fibroblasts. The imbalance between pro-inflammatory and anti-inflammatory cytokines, leads to the CRS, an excessive and damaging host inflammation [28]. As a consequence of CRS [29], due to a severe infection of SARS-CoV-2 of the respiratory epithelium, the ARDS was observed in COVID-19 [30]. Edema and an IL-1β mediated proinflammatory response were increased in the lung parenchyma. Macrophages and dendritic cells produce IL-1β through macro-molecular complexes called inflammasomes, including the major element present in the pulmonary tissue and the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome [20]. Following a precise stimulus, the activation and recruitment domain of caspase (ASC) and the catalytically inactive procaspase-1 assemble, the procaspase-1 turns into active caspase-1, the inactive pro-IL-1β matures in IL-1β and the NLRP3 inflammasome is activated. The NLRP3 inflammasomes and IL-1β driven proinflammatory cascades correlate with worsening of several respiratory diseases, including COVID-19.\nPatients affected by obesity showed a severe consequence of COVID-19 [31], due to the high concentrations of TNF-α, MCP-1 and IL-6 produced in the meantime by visceral and subcutaneous adipose tissue and by innate immunity [32]. Moreover, leptin, released by adipose tissue, helps to increase inflammatory milieu with a dysregulation of the immune response [33].\nThis umbrella review seeks to answer the question of whether a nutritional approach can be used to enhance the immune system’s response to obesity in obese patients affected by COVID-19.\nImmunonutrition has been based on the concept that malnutrition impairs immune function, used to modify inflammatory or immune responses. This concept may be applied to any situation in which a supply of specific nutrients is necessary to modify inflammatory or immune responses. Immunonutrients can promote patient recovery by inhibiting inflammatory responses and regulating immune function. Therefore, immunonutrition involves feeding enriched with various pharmaconutrients (arginine, glutamine, omega-3-fatty acids, ribonucleotides and certain trace elements and antioxidants compound, vitamins and minerals) to modulate inflammatory responses, the acquired immune response, and to improve patient outcomes [34].\nPersonalized immunonutrition for patients with obesity should be the first therapeutic choice to reduce the risk of infections and the disease course in COVID-19 patients. That therapeutic strategy could be effective in case of other potential epidemic infections. It would also allow a reduction of the enormous medical care cost supported by the National Health Service."}

{"project":"LitCovid-PD-GO-BP","denotations":[{"id":"T13","span":{"begin":15,"end":27},"obj":"http://purl.obolibrary.org/obo/GO_0006954"},{"id":"T14","span":{"begin":203,"end":218},"obj":"http://purl.obolibrary.org/obo/GO_0006955"},{"id":"T15","span":{"begin":435,"end":448},"obj":"http://purl.obolibrary.org/obo/GO_0045087"},{"id":"T16","span":{"begin":477,"end":501},"obj":"http://purl.obolibrary.org/obo/GO_0002250"},{"id":"T17","span":{"begin":486,"end":501},"obj":"http://purl.obolibrary.org/obo/GO_0006955"},{"id":"T18","span":{"begin":566,"end":579},"obj":"http://purl.obolibrary.org/obo/GO_0045087"},{"id":"T19","span":{"begin":792,"end":805},"obj":"http://purl.obolibrary.org/obo/GO_0045087"},{"id":"T20","span":{"begin":1236,"end":1248},"obj":"http://purl.obolibrary.org/obo/GO_0006954"},{"id":"T21","span":{"begin":1316,"end":1329},"obj":"http://purl.obolibrary.org/obo/GO_0045087"},{"id":"T22","span":{"begin":2183,"end":2200},"obj":"http://purl.obolibrary.org/obo/GO_0019882"},{"id":"T23","span":{"begin":2323,"end":2355},"obj":"http://purl.obolibrary.org/obo/GO_0046776"},{"id":"T24","span":{"begin":2357,"end":2360},"obj":"http://purl.obolibrary.org/obo/GO_0046776"},{"id":"T25","span":{"begin":2418,"end":2435},"obj":"http://purl.obolibrary.org/obo/GO_0019882"},{"id":"T26","span":{"begin":2508,"end":2511},"obj":"http://purl.obolibrary.org/obo/GO_0046776"},{"id":"T27","span":{"begin":2627,"end":2650},"obj":"http://purl.obolibrary.org/obo/GO_0046651"},{"id":"T28","span":{"begin":3320,"end":3361},"obj":"http://purl.obolibrary.org/obo/GO_0035556"},{"id":"T29","span":{"begin":3334,"end":3353},"obj":"http://purl.obolibrary.org/obo/GO_0007165"},{"id":"T30","span":{"begin":3341,"end":3353},"obj":"http://purl.obolibrary.org/obo/GO_0009293"},{"id":"T31","span":{"begin":3424,"end":3438},"obj":"http://purl.obolibrary.org/obo/GO_0016310"},{"id":"T32","span":{"begin":3443,"end":3456},"obj":"http://purl.obolibrary.org/obo/GO_0006351"},{"id":"T33","span":{"begin":3548,"end":3561},"obj":"http://purl.obolibrary.org/obo/GO_0006351"},{"id":"T34","span":{"begin":3660,"end":3679},"obj":"http://purl.obolibrary.org/obo/GO_0007165"},{"id":"T35","span":{"begin":3660,"end":3670},"obj":"http://purl.obolibrary.org/obo/GO_0023052"},{"id":"T36","span":{"begin":4091,"end":4110},"obj":"http://purl.obolibrary.org/obo/GO_0002377"},{"id":"T37","span":{"begin":4127,"end":4151},"obj":"http://purl.obolibrary.org/obo/GO_0050766"},{"id":"T38","span":{"begin":4139,"end":4151},"obj":"http://purl.obolibrary.org/obo/GO_0006909"},{"id":"T39","span":{"begin":4196,"end":4206},"obj":"http://purl.obolibrary.org/obo/GO_0023052"},{"id":"T40","span":{"begin":4227,"end":4248},"obj":"http://purl.obolibrary.org/obo/GO_0000981"},{"id":"T41","span":{"begin":4227,"end":4240},"obj":"http://purl.obolibrary.org/obo/GO_0006351"},{"id":"T42","span":{"begin":4341,"end":4356},"obj":"http://purl.obolibrary.org/obo/GO_0006351"},{"id":"T43","span":{"begin":4435,"end":4441},"obj":"http://purl.obolibrary.org/obo/GO_0040007"},{"id":"T44","span":{"begin":4473,"end":4485},"obj":"http://purl.obolibrary.org/obo/GO_0006954"},{"id":"T45","span":{"begin":4497,"end":4505},"obj":"http://purl.obolibrary.org/obo/GO_0070265"},{"id":"T46","span":{"begin":4497,"end":4505},"obj":"http://purl.obolibrary.org/obo/GO_0019835"},{"id":"T47","span":{"begin":4497,"end":4505},"obj":"http://purl.obolibrary.org/obo/GO_0008219"},{"id":"T48","span":{"begin":4497,"end":4505},"obj":"http://purl.obolibrary.org/obo/GO_0001906"},{"id":"T49","span":{"begin":4623,"end":4632},"obj":"http://purl.obolibrary.org/obo/GO_0097194"},{"id":"T50","span":{"begin":4623,"end":4632},"obj":"http://purl.obolibrary.org/obo/GO_0006915"},{"id":"T51","span":{"begin":4679,"end":4691},"obj":"http://purl.obolibrary.org/obo/GO_0006954"},{"id":"T52","span":{"begin":4870,"end":4889},"obj":"http://purl.obolibrary.org/obo/GO_0006952"},{"id":"T53","span":{"begin":5626,"end":5648},"obj":"http://purl.obolibrary.org/obo/GO_0045087"},{"id":"T54","span":{"begin":5633,"end":5648},"obj":"http://purl.obolibrary.org/obo/GO_0006955"},{"id":"T55","span":{"begin":5895,"end":5898},"obj":"http://purl.obolibrary.org/obo/GO_0046776"},{"id":"T56","span":{"begin":6091,"end":6099},"obj":"http://purl.obolibrary.org/obo/GO_0070265"},{"id":"T57","span":{"begin":6091,"end":6099},"obj":"http://purl.obolibrary.org/obo/GO_0019835"},{"id":"T58","span":{"begin":6091,"end":6099},"obj":"http://purl.obolibrary.org/obo/GO_0008219"},{"id":"T59","span":{"begin":6091,"end":6099},"obj":"http://purl.obolibrary.org/obo/GO_0001906"},{"id":"T60","span":{"begin":6114,"end":6126},"obj":"http://purl.obolibrary.org/obo/GO_0006954"},{"id":"T61","span":{"begin":6344,"end":6356},"obj":"http://purl.obolibrary.org/obo/GO_0006954"},{"id":"T62","span":{"begin":6693,"end":6709},"obj":"http://purl.obolibrary.org/obo/GO_0016032"},{"id":"T63","span":{"begin":7367,"end":7378},"obj":"http://purl.obolibrary.org/obo/GO_0006897"},{"id":"T64","span":{"begin":7383,"end":7398},"obj":"http://purl.obolibrary.org/obo/GO_0061025"},{"id":"T65","span":{"begin":7651,"end":7682},"obj":"http://purl.obolibrary.org/obo/GO_0015804"},{"id":"T66","span":{"begin":7723,"end":7735},"obj":"http://purl.obolibrary.org/obo/GO_0006954"},{"id":"T67","span":{"begin":7862,"end":7866},"obj":"http://purl.obolibrary.org/obo/GO_0004707"},{"id":"T68","span":{"begin":7901,"end":7913},"obj":"http://purl.obolibrary.org/obo/GO_0006954"},{"id":"T69","span":{"begin":8082,"end":8106},"obj":"http://purl.obolibrary.org/obo/GO_0002250"},{"id":"T70","span":{"begin":8091,"end":8106},"obj":"http://purl.obolibrary.org/obo/GO_0006955"},{"id":"T71","span":{"begin":8482,"end":8497},"obj":"http://purl.obolibrary.org/obo/GO_0006955"},{"id":"T72","span":{"begin":9146,"end":9173},"obj":"http://purl.obolibrary.org/obo/GO_0008217"},{"id":"T73","span":{"begin":9199,"end":9211},"obj":"http://purl.obolibrary.org/obo/GO_0042311"},{"id":"T74","span":{"begin":9213,"end":9224},"obj":"http://purl.obolibrary.org/obo/GO_0035815"},{"id":"T75","span":{"begin":9344,"end":9353},"obj":"http://purl.obolibrary.org/obo/GO_0023052"},{"id":"T76","span":{"begin":9591,"end":9612},"obj":"http://purl.obolibrary.org/obo/GO_0006954"},{"id":"T77","span":{"begin":10269,"end":10281},"obj":"http://purl.obolibrary.org/obo/GO_0006954"},{"id":"T78","span":{"begin":10314,"end":10326},"obj":"http://purl.obolibrary.org/obo/GO_0009405"},{"id":"T79","span":{"begin":10932,"end":10944},"obj":"http://purl.obolibrary.org/obo/GO_0006954"},{"id":"T80","span":{"begin":12094,"end":12109},"obj":"http://purl.obolibrary.org/obo/GO_0045087"},{"id":"T81","span":{"begin":12228,"end":12243},"obj":"http://purl.obolibrary.org/obo/GO_0006955"},{"id":"T82","span":{"begin":12557,"end":12573},"obj":"http://purl.obolibrary.org/obo/GO_0006955"},{"id":"T83","span":{"begin":12699,"end":12715},"obj":"http://purl.obolibrary.org/obo/GO_0006955"},{"id":"T84","span":{"begin":12765,"end":12798},"obj":"http://purl.obolibrary.org/obo/GO_0050728"},{"id":"T85","span":{"begin":12776,"end":12798},"obj":"http://purl.obolibrary.org/obo/GO_0006954"},{"id":"T86","span":{"begin":13063,"end":13085},"obj":"http://purl.obolibrary.org/obo/GO_0006954"},{"id":"T87","span":{"begin":13091,"end":13115},"obj":"http://purl.obolibrary.org/obo/GO_0002250"},{"id":"T88","span":{"begin":13100,"end":13115},"obj":"http://purl.obolibrary.org/obo/GO_0006955"}],"text":"Immune system, inflammation and COVID-19\nThe immune system protects the human body from infections by a series of pathogen (bacteria, viruses, fungi, parasites) [5]. A self-tolerance system prevents the immune response from damaging human tissues. The immune system is always active, carrying out surveillance. The defense to first exposure to the pathogen is represented by two complementary and cooperating functional divisions, the innate immune and, on the other hand, the adaptive immune response, that represents a response based on previous exposure [6]. The innate immune system is represented by dendritic cells, macrophages and neutrophils, with phagocytic activity, and by eosinophils, mast cells and natural killer cells, which release specific soluble antimicrobial factors. The innate immune system includes physical barriers, represented by interconnected epithelial cells (e.g. tight junctions and cellular interactions mediated by cadherin), epithelial cilia and the mucus layer of the respiratory, gastrointestinal and genitourinary epithelium. Moreover, soluble proteins and small bioactive molecules such as complement proteins, defensins and ficolins 1-3, pro-inflammatory cytokines, chemokines, lipid mediators of inflammation, membrane-bound receptors and cytoplasmic proteins are part of the innate immune system. Both innate and adaptive immunity is mediated by leukocytes. Lymphocytes circulate between the blood system and the lymphatic system, passing through the peripheral lymphoid organs, which includes the spleen, tonsils, appendix, lymph nodes and gut-associated lymphoid tissue (GALT). From a common lymphoid progenitor, four major populations of mature lymphocytes are derived, that belong to the adaptive immune system: of B lymphocytes (B cells) and T lymphocytes (T cells), natural killer (NK) cells, and NK-T cells. T-cells can be further categorized to cytotoxic T-cells (TC cells), helper T-cells (Th) and suppressor T-cells. The specific antigenic receptors of the adaptive response are represented by genes that code for an intact T cell receptor (TCR) and immunoglobulin genes (B cell antigen receptor; Ig). TCR is capable of binding the antigen processed by antigen-presenting cells (APC). Dendritic cells represent the most powerful class of APC, and express molecules of the major histocompatibility complex (MHC) of class I and II, necessary for the recognition of the antigen processed by TCR on T cells [7].\nFollowing the presentation of viral antigens via MHC II, the T helper CD4+ lymphocytes are activated and switch to the T helper 1 phenotype [8].\nThe activated T helper lymphocytes proliferate and release cytokines: after stimulation by antigen and APC, the Th0 cells begin to produce interleukin (IL)-2. Meanwhile, Th cells differentiate into Th1, Th2 and Th17 according to the nature of the cytokines present in the activation site: IL-12 produced by macrophages and type I Interferon (IFN) or NK cells induce differentiation towards Th1, IL-4 produced by NK1.1 + T cells, basophils or mast cells induce differentiation towards Th2, and IL-1b, IL-23, TGFβ and IL-6 induce differentiation towards Th17 [9]. Th17 cells produce IL-17 and IL-22, and antigen-induced Treg (iTreg).\nThe binding of the cytokine to its transmembrane cell surface receptor activates an intracellular signal transduction pathway, generally a Janus kinase (Jak), which, via a kinase cascade, phosphorylates its transcription protein (STAT). Phosphorylated STAT dimers and moves to the nucleus, initiating a new gene transcription. Mutation of STAT1 increases susceptibility to virus infections because it is involved in various signalling pathways, including IFN-α/β, IFN- γ, IFN-l, IL-2, IL-3, IL-6, IL-9, IL-10, IL-11, IL-12, IL-15, IL-21, IL-22, IL-26 and IL-27 [10], and chemokines of several types such as C-X-C motif chemokine ligand 10 (CXCL-10), Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted (RANTES)/Chemokine (C–C motif) ligand 5 (CCL-5), Monocyte Chemoattractant Protein-1 (MCP-1) [11]. IFN-γ promotes antigen-specific antibody production, increasing the activity of phagocytosis. In the meantime, PRRs trigger inflammatory signalling, with activation of transcription factors like nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). NFκB is the key transcriptional regulator of many pro-inflammatory cytokines, adhesion molecules, chemokines, growth factors and other mediators of inflammation, as tumour necrosis factor (TNF), interleukins 1 (IL-1β), 6 (IL-6), and 12 (IL-12), promotes cellular proliferation and protects against apoptosis providing a mechanism that determines chronic inflammation. The recognition of pathogens is achieved through the presence of pattern recognition receptors (PRRs) [12]. PRRs identify the microbe-associated molecular patterns (MAMPs), and defensive responses is activated. PRRs include Toll-like receptors (TLRs), that are able to recognize viral DNA, viral double-stranded RNA and viral single-stranded RNA. TLRs are expressed on macrophages, dendritic cells, neutrophils, eosinophils, epithelial cells and keratinocytes. In particular, intracellular TLR-7 and TLR-8 allow the innate recognition of the single-stranded RNA of coronaviruses [13]. Intracellular and extracellular PRRs recognized spike glycoprotein, of the coronavirus coat, starting the inflammatory process, through the NFκB pathway [14]. Moreover, Nucleotide-Binding Domain, Leucine-Rich Repeat (NLR) proteins have also been identified, and NALP3 (NACHT, LRR and PYD domains-containing protein 3) has a special function in the innate immune response [15]. The processes involved in antiviral immunity is shown in Fig. 1.\nFig. 1 Graphical representation of antiviral SARS-Coronavirus 2 immunity. B: B lymphocyte; CTL: cytotoxic; T lymphocyte; IFN: interferon; Ig: immunoglobulin; IL: interleukin; MHC: major histocompatibility class; NFκB: nuclear factor kappa-light- chain- enhancer of activated B cells; NK: natural killer cell; Th: helper T lymphocyte; TLR: Toll-like receptor; TNF: tumour necrosis factor\nNormal inflammation is self-limiting because the production of pro-inflammatory cytokines (Th1 cytokines) is followed almost immediately by the production of anti-inflammatory cytokines (Th2 cytokines; IL-1, IL-10, IL-13, etc.). Chronic inflammation seems to result when the initiating factors persist, or there is some sort of failure of the resolution process.\nDysfunction of the immune system and the loss of homeostatic equilibrium between TREG cells (IL- 10) and Th17 cells (IL-17) was observed in different pathological situations [16], and it is believed to increase the risk of viral infections, including SARS- coronavirus 2 (SARS-CoV-2) [14].\nSARS-CoV-2 is an enveloped positive-strand RNA virus in the family Coronaviridae, group 2b, which encodes the viral replicase and four structural proteins: spike (S), envelope (E) and membrane (M), present in the viral envelope, and nucleocapsid (N) [17].\nThe access route of SARS-CoV-2 is represented by a hydrophobic pocket of the extracellular catalytic domain of Angiotensin-converting enzyme 2 (ACE2) [18]. SARS-CoV peak S protein trimers bind ACE2, expressed in endothelial cells of the vasculature and in the epithelia of the lungs, intestine, heart, brain and kidney. SARS-CoV-2 enters the cell for endocytosis and membrane fusion. Once the virus has infected the cell, it follows a downregulation of ACE2 with a consequent local increase in the levels of Ang II, and the development of acute respiratory distress syndrome (ARDS) [19]. The role of ACE2 in the gut, for expression of neutral amino acid transporters, could explain diarrhoea and intestinal inflammation observed in COVID-19. Moreover, SARS-CoV2 protein E activates the NFκB inflammatory pathway with the consequent activation of MAPK p38, resulting in exacerbation of inflammation and immunopathology [20]. Following the SARS-CoV-2 infection, in the incubation stage and in the non-serious form of COVID-19, the immune system activates the specific adaptive immune response to eliminate the virus, which should be sufficient to block viral propagation and disease progression. The antiviral system functions well in the presence of general good health and an adequate genetic background. However, the presence of concomitant pathologies (obesity, cardiovascular diseases, diabetes, neurodegenerative diseases and cancer), malnutrition, and impaired immune response determine the spread of the virus and a massive destruction of the affected tissues, especially in organs that have high ACE2 expression [21]. As noted earlier, SARS-CoV-2 enters the cell via ACE2; that inactivates des-Arg bradykinin, which is a potent ligand of the bradykinin receptor type 1 (BDKRB1).This receptor, localized on endothelial cells, is up-regulated by inflammatory cytokines, which is unlike the B2 receptor, that is constituently expressed and is the receptor for bradykinin (BDK). BDK is produced from an inactive pre-protein kininogen through activation by the serine protease kallikrein; in addition, it is considered a potent regulator of blood pressure [22], because it induces vasodilation, natriuresis, and hypotension upon activation of the BDKRB2 receptor. BDK is strongly integrated with the RAS, and the BDK receptor signaling is increased by angiotensin’s action [23].\nInterestingly, ACE has a higher affinity for BDK [24] and therefore in conditions where ACE is low, the vasopressor system is moved toward a BDK-directed hypotensive axis. BDK takes part in the inflammatory response after injury and acts to induce pain via stimulation of the BDKRB1 receptor, which also causes neutrophil recruitment and a major vascular permeability [25, 26].\nDuring the infection, as long as the virus persists, there is dysfunction of ACE2 function, leading to the dysregulation of the kinin-kallikrein pathway and thus causing the angioedema [27]. Some evidence that the edema is bradykinin-generated includes resistance to corticosteroids, epinephrine, and antihistamines in the management of reducing the pulmonary edema in COVID-19 patients. In fact, the so called Bradykinin Storm is likely responsible for most of the observed COVID-19 symptoms.\nInflammation plays a fundamental role in the pathogenesis and progression of COVID-19, ranging from common colds to fatal cases of pneumonia due to the cytokine release syndrome (CRS) that affected patients, determining the severe conditions. In COVID-19 the homeostatic equilibrium between TREG cells (IL-10) and Th17 cells (IL-17) is broken: inflammatory cytokine levels (IL-1, TNF) are elevated in the lungs of COVID-19 patients, resulting in an increase in HA-synthase-2 (HAS2) in alveolar epithelial cells CD31+, EpCAM+ and fibroblasts. The imbalance between pro-inflammatory and anti-inflammatory cytokines, leads to the CRS, an excessive and damaging host inflammation [28]. As a consequence of CRS [29], due to a severe infection of SARS-CoV-2 of the respiratory epithelium, the ARDS was observed in COVID-19 [30]. Edema and an IL-1β mediated proinflammatory response were increased in the lung parenchyma. Macrophages and dendritic cells produce IL-1β through macro-molecular complexes called inflammasomes, including the major element present in the pulmonary tissue and the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome [20]. Following a precise stimulus, the activation and recruitment domain of caspase (ASC) and the catalytically inactive procaspase-1 assemble, the procaspase-1 turns into active caspase-1, the inactive pro-IL-1β matures in IL-1β and the NLRP3 inflammasome is activated. The NLRP3 inflammasomes and IL-1β driven proinflammatory cascades correlate with worsening of several respiratory diseases, including COVID-19.\nPatients affected by obesity showed a severe consequence of COVID-19 [31], due to the high concentrations of TNF-α, MCP-1 and IL-6 produced in the meantime by visceral and subcutaneous adipose tissue and by innate immunity [32]. Moreover, leptin, released by adipose tissue, helps to increase inflammatory milieu with a dysregulation of the immune response [33].\nThis umbrella review seeks to answer the question of whether a nutritional approach can be used to enhance the immune system’s response to obesity in obese patients affected by COVID-19.\nImmunonutrition has been based on the concept that malnutrition impairs immune function, used to modify inflammatory or immune responses. This concept may be applied to any situation in which a supply of specific nutrients is necessary to modify inflammatory or immune responses. Immunonutrients can promote patient recovery by inhibiting inflammatory responses and regulating immune function. Therefore, immunonutrition involves feeding enriched with various pharmaconutrients (arginine, glutamine, omega-3-fatty acids, ribonucleotides and certain trace elements and antioxidants compound, vitamins and minerals) to modulate inflammatory responses, the acquired immune response, and to improve patient outcomes [34].\nPersonalized immunonutrition for patients with obesity should be the first therapeutic choice to reduce the risk of infections and the disease course in COVID-19 patients. That therapeutic strategy could be effective in case of other potential epidemic infections. It would also allow a reduction of the enormous medical care cost supported by the National Health Service."}

{"project":"LitCovid-sentences","denotations":[{"id":"T28","span":{"begin":0,"end":40},"obj":"Sentence"},{"id":"T29","span":{"begin":41,"end":165},"obj":"Sentence"},{"id":"T30","span":{"begin":166,"end":247},"obj":"Sentence"},{"id":"T31","span":{"begin":248,"end":310},"obj":"Sentence"},{"id":"T32","span":{"begin":311,"end":561},"obj":"Sentence"},{"id":"T33","span":{"begin":562,"end":787},"obj":"Sentence"},{"id":"T34","span":{"begin":788,"end":1062},"obj":"Sentence"},{"id":"T35","span":{"begin":1063,"end":1337},"obj":"Sentence"},{"id":"T36","span":{"begin":1338,"end":1398},"obj":"Sentence"},{"id":"T37","span":{"begin":1399,"end":1620},"obj":"Sentence"},{"id":"T38","span":{"begin":1621,"end":1855},"obj":"Sentence"},{"id":"T39","span":{"begin":1856,"end":1967},"obj":"Sentence"},{"id":"T40","span":{"begin":1968,"end":2152},"obj":"Sentence"},{"id":"T41","span":{"begin":2153,"end":2235},"obj":"Sentence"},{"id":"T42","span":{"begin":2236,"end":2458},"obj":"Sentence"},{"id":"T43","span":{"begin":2459,"end":2603},"obj":"Sentence"},{"id":"T44","span":{"begin":2604,"end":2762},"obj":"Sentence"},{"id":"T45","span":{"begin":2763,"end":3165},"obj":"Sentence"},{"id":"T46","span":{"begin":3166,"end":3235},"obj":"Sentence"},{"id":"T47","span":{"begin":3236,"end":3472},"obj":"Sentence"},{"id":"T48","span":{"begin":3473,"end":3562},"obj":"Sentence"},{"id":"T49","span":{"begin":3563,"end":4058},"obj":"Sentence"},{"id":"T50","span":{"begin":4059,"end":4152},"obj":"Sentence"},{"id":"T51","span":{"begin":4153,"end":4324},"obj":"Sentence"},{"id":"T52","span":{"begin":4325,"end":4692},"obj":"Sentence"},{"id":"T53","span":{"begin":4693,"end":4800},"obj":"Sentence"},{"id":"T54","span":{"begin":4801,"end":4903},"obj":"Sentence"},{"id":"T55","span":{"begin":4904,"end":5039},"obj":"Sentence"},{"id":"T56","span":{"begin":5040,"end":5153},"obj":"Sentence"},{"id":"T57","span":{"begin":5154,"end":5277},"obj":"Sentence"},{"id":"T58","span":{"begin":5278,"end":5436},"obj":"Sentence"},{"id":"T59","span":{"begin":5437,"end":5654},"obj":"Sentence"},{"id":"T60","span":{"begin":5655,"end":5719},"obj":"Sentence"},{"id":"T61","span":{"begin":5720,"end":5793},"obj":"Sentence"},{"id":"T62","span":{"begin":5794,"end":5796},"obj":"Sentence"},{"id":"T63","span":{"begin":5797,"end":6058},"obj":"Sentence"},{"id":"T64","span":{"begin":6059,"end":6106},"obj":"Sentence"},{"id":"T65","span":{"begin":6107,"end":6335},"obj":"Sentence"},{"id":"T66","span":{"begin":6336,"end":6469},"obj":"Sentence"},{"id":"T67","span":{"begin":6470,"end":6759},"obj":"Sentence"},{"id":"T68","span":{"begin":6760,"end":7015},"obj":"Sentence"},{"id":"T69","span":{"begin":7016,"end":7171},"obj":"Sentence"},{"id":"T70","span":{"begin":7172,"end":7335},"obj":"Sentence"},{"id":"T71","span":{"begin":7336,"end":7399},"obj":"Sentence"},{"id":"T72","span":{"begin":7400,"end":7603},"obj":"Sentence"},{"id":"T73","span":{"begin":7604,"end":7757},"obj":"Sentence"},{"id":"T74","span":{"begin":7758,"end":7939},"obj":"Sentence"},{"id":"T75","span":{"begin":7940,"end":8209},"obj":"Sentence"},{"id":"T76","span":{"begin":8210,"end":8320},"obj":"Sentence"},{"id":"T77","span":{"begin":8321,"end":8640},"obj":"Sentence"},{"id":"T78","span":{"begin":8641,"end":8997},"obj":"Sentence"},{"id":"T79","span":{"begin":8998,"end":9281},"obj":"Sentence"},{"id":"T80","span":{"begin":9282,"end":9396},"obj":"Sentence"},{"id":"T81","span":{"begin":9397,"end":9568},"obj":"Sentence"},{"id":"T82","span":{"begin":9569,"end":9774},"obj":"Sentence"},{"id":"T83","span":{"begin":9775,"end":9965},"obj":"Sentence"},{"id":"T84","span":{"begin":9966,"end":10162},"obj":"Sentence"},{"id":"T85","span":{"begin":10163,"end":10268},"obj":"Sentence"},{"id":"T86","span":{"begin":10269,"end":10511},"obj":"Sentence"},{"id":"T87","span":{"begin":10512,"end":10810},"obj":"Sentence"},{"id":"T88","span":{"begin":10811,"end":10950},"obj":"Sentence"},{"id":"T89","span":{"begin":10951,"end":11091},"obj":"Sentence"},{"id":"T90","span":{"begin":11092,"end":11183},"obj":"Sentence"},{"id":"T91","span":{"begin":11184,"end":11476},"obj":"Sentence"},{"id":"T92","span":{"begin":11477,"end":11742},"obj":"Sentence"},{"id":"T93","span":{"begin":11743,"end":11886},"obj":"Sentence"},{"id":"T94","span":{"begin":11887,"end":12115},"obj":"Sentence"},{"id":"T95","span":{"begin":12116,"end":12249},"obj":"Sentence"},{"id":"T96","span":{"begin":12250,"end":12436},"obj":"Sentence"},{"id":"T97","span":{"begin":12437,"end":12574},"obj":"Sentence"},{"id":"T98","span":{"begin":12575,"end":12716},"obj":"Sentence"},{"id":"T99","span":{"begin":12717,"end":12830},"obj":"Sentence"},{"id":"T100","span":{"begin":12831,"end":13154},"obj":"Sentence"},{"id":"T101","span":{"begin":13155,"end":13326},"obj":"Sentence"},{"id":"T102","span":{"begin":13327,"end":13419},"obj":"Sentence"},{"id":"T103","span":{"begin":13420,"end":13527},"obj":"Sentence"}],"namespaces":[{"prefix":"_base","uri":"http://pubannotation.org/ontology/tao.owl#"}],"text":"Immune system, inflammation and COVID-19\nThe immune system protects the human body from infections by a series of pathogen (bacteria, viruses, fungi, parasites) [5]. A self-tolerance system prevents the immune response from damaging human tissues. The immune system is always active, carrying out surveillance. The defense to first exposure to the pathogen is represented by two complementary and cooperating functional divisions, the innate immune and, on the other hand, the adaptive immune response, that represents a response based on previous exposure [6]. The innate immune system is represented by dendritic cells, macrophages and neutrophils, with phagocytic activity, and by eosinophils, mast cells and natural killer cells, which release specific soluble antimicrobial factors. The innate immune system includes physical barriers, represented by interconnected epithelial cells (e.g. tight junctions and cellular interactions mediated by cadherin), epithelial cilia and the mucus layer of the respiratory, gastrointestinal and genitourinary epithelium. Moreover, soluble proteins and small bioactive molecules such as complement proteins, defensins and ficolins 1-3, pro-inflammatory cytokines, chemokines, lipid mediators of inflammation, membrane-bound receptors and cytoplasmic proteins are part of the innate immune system. Both innate and adaptive immunity is mediated by leukocytes. Lymphocytes circulate between the blood system and the lymphatic system, passing through the peripheral lymphoid organs, which includes the spleen, tonsils, appendix, lymph nodes and gut-associated lymphoid tissue (GALT). From a common lymphoid progenitor, four major populations of mature lymphocytes are derived, that belong to the adaptive immune system: of B lymphocytes (B cells) and T lymphocytes (T cells), natural killer (NK) cells, and NK-T cells. T-cells can be further categorized to cytotoxic T-cells (TC cells), helper T-cells (Th) and suppressor T-cells. The specific antigenic receptors of the adaptive response are represented by genes that code for an intact T cell receptor (TCR) and immunoglobulin genes (B cell antigen receptor; Ig). TCR is capable of binding the antigen processed by antigen-presenting cells (APC). Dendritic cells represent the most powerful class of APC, and express molecules of the major histocompatibility complex (MHC) of class I and II, necessary for the recognition of the antigen processed by TCR on T cells [7].\nFollowing the presentation of viral antigens via MHC II, the T helper CD4+ lymphocytes are activated and switch to the T helper 1 phenotype [8].\nThe activated T helper lymphocytes proliferate and release cytokines: after stimulation by antigen and APC, the Th0 cells begin to produce interleukin (IL)-2. Meanwhile, Th cells differentiate into Th1, Th2 and Th17 according to the nature of the cytokines present in the activation site: IL-12 produced by macrophages and type I Interferon (IFN) or NK cells induce differentiation towards Th1, IL-4 produced by NK1.1 + T cells, basophils or mast cells induce differentiation towards Th2, and IL-1b, IL-23, TGFβ and IL-6 induce differentiation towards Th17 [9]. Th17 cells produce IL-17 and IL-22, and antigen-induced Treg (iTreg).\nThe binding of the cytokine to its transmembrane cell surface receptor activates an intracellular signal transduction pathway, generally a Janus kinase (Jak), which, via a kinase cascade, phosphorylates its transcription protein (STAT). Phosphorylated STAT dimers and moves to the nucleus, initiating a new gene transcription. Mutation of STAT1 increases susceptibility to virus infections because it is involved in various signalling pathways, including IFN-α/β, IFN- γ, IFN-l, IL-2, IL-3, IL-6, IL-9, IL-10, IL-11, IL-12, IL-15, IL-21, IL-22, IL-26 and IL-27 [10], and chemokines of several types such as C-X-C motif chemokine ligand 10 (CXCL-10), Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted (RANTES)/Chemokine (C–C motif) ligand 5 (CCL-5), Monocyte Chemoattractant Protein-1 (MCP-1) [11]. IFN-γ promotes antigen-specific antibody production, increasing the activity of phagocytosis. In the meantime, PRRs trigger inflammatory signalling, with activation of transcription factors like nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). NFκB is the key transcriptional regulator of many pro-inflammatory cytokines, adhesion molecules, chemokines, growth factors and other mediators of inflammation, as tumour necrosis factor (TNF), interleukins 1 (IL-1β), 6 (IL-6), and 12 (IL-12), promotes cellular proliferation and protects against apoptosis providing a mechanism that determines chronic inflammation. The recognition of pathogens is achieved through the presence of pattern recognition receptors (PRRs) [12]. PRRs identify the microbe-associated molecular patterns (MAMPs), and defensive responses is activated. PRRs include Toll-like receptors (TLRs), that are able to recognize viral DNA, viral double-stranded RNA and viral single-stranded RNA. TLRs are expressed on macrophages, dendritic cells, neutrophils, eosinophils, epithelial cells and keratinocytes. In particular, intracellular TLR-7 and TLR-8 allow the innate recognition of the single-stranded RNA of coronaviruses [13]. Intracellular and extracellular PRRs recognized spike glycoprotein, of the coronavirus coat, starting the inflammatory process, through the NFκB pathway [14]. Moreover, Nucleotide-Binding Domain, Leucine-Rich Repeat (NLR) proteins have also been identified, and NALP3 (NACHT, LRR and PYD domains-containing protein 3) has a special function in the innate immune response [15]. The processes involved in antiviral immunity is shown in Fig. 1.\nFig. 1 Graphical representation of antiviral SARS-Coronavirus 2 immunity. B: B lymphocyte; CTL: cytotoxic; T lymphocyte; IFN: interferon; Ig: immunoglobulin; IL: interleukin; MHC: major histocompatibility class; NFκB: nuclear factor kappa-light- chain- enhancer of activated B cells; NK: natural killer cell; Th: helper T lymphocyte; TLR: Toll-like receptor; TNF: tumour necrosis factor\nNormal inflammation is self-limiting because the production of pro-inflammatory cytokines (Th1 cytokines) is followed almost immediately by the production of anti-inflammatory cytokines (Th2 cytokines; IL-1, IL-10, IL-13, etc.). Chronic inflammation seems to result when the initiating factors persist, or there is some sort of failure of the resolution process.\nDysfunction of the immune system and the loss of homeostatic equilibrium between TREG cells (IL- 10) and Th17 cells (IL-17) was observed in different pathological situations [16], and it is believed to increase the risk of viral infections, including SARS- coronavirus 2 (SARS-CoV-2) [14].\nSARS-CoV-2 is an enveloped positive-strand RNA virus in the family Coronaviridae, group 2b, which encodes the viral replicase and four structural proteins: spike (S), envelope (E) and membrane (M), present in the viral envelope, and nucleocapsid (N) [17].\nThe access route of SARS-CoV-2 is represented by a hydrophobic pocket of the extracellular catalytic domain of Angiotensin-converting enzyme 2 (ACE2) [18]. SARS-CoV peak S protein trimers bind ACE2, expressed in endothelial cells of the vasculature and in the epithelia of the lungs, intestine, heart, brain and kidney. SARS-CoV-2 enters the cell for endocytosis and membrane fusion. Once the virus has infected the cell, it follows a downregulation of ACE2 with a consequent local increase in the levels of Ang II, and the development of acute respiratory distress syndrome (ARDS) [19]. The role of ACE2 in the gut, for expression of neutral amino acid transporters, could explain diarrhoea and intestinal inflammation observed in COVID-19. Moreover, SARS-CoV2 protein E activates the NFκB inflammatory pathway with the consequent activation of MAPK p38, resulting in exacerbation of inflammation and immunopathology [20]. Following the SARS-CoV-2 infection, in the incubation stage and in the non-serious form of COVID-19, the immune system activates the specific adaptive immune response to eliminate the virus, which should be sufficient to block viral propagation and disease progression. The antiviral system functions well in the presence of general good health and an adequate genetic background. However, the presence of concomitant pathologies (obesity, cardiovascular diseases, diabetes, neurodegenerative diseases and cancer), malnutrition, and impaired immune response determine the spread of the virus and a massive destruction of the affected tissues, especially in organs that have high ACE2 expression [21]. As noted earlier, SARS-CoV-2 enters the cell via ACE2; that inactivates des-Arg bradykinin, which is a potent ligand of the bradykinin receptor type 1 (BDKRB1).This receptor, localized on endothelial cells, is up-regulated by inflammatory cytokines, which is unlike the B2 receptor, that is constituently expressed and is the receptor for bradykinin (BDK). BDK is produced from an inactive pre-protein kininogen through activation by the serine protease kallikrein; in addition, it is considered a potent regulator of blood pressure [22], because it induces vasodilation, natriuresis, and hypotension upon activation of the BDKRB2 receptor. BDK is strongly integrated with the RAS, and the BDK receptor signaling is increased by angiotensin’s action [23].\nInterestingly, ACE has a higher affinity for BDK [24] and therefore in conditions where ACE is low, the vasopressor system is moved toward a BDK-directed hypotensive axis. BDK takes part in the inflammatory response after injury and acts to induce pain via stimulation of the BDKRB1 receptor, which also causes neutrophil recruitment and a major vascular permeability [25, 26].\nDuring the infection, as long as the virus persists, there is dysfunction of ACE2 function, leading to the dysregulation of the kinin-kallikrein pathway and thus causing the angioedema [27]. Some evidence that the edema is bradykinin-generated includes resistance to corticosteroids, epinephrine, and antihistamines in the management of reducing the pulmonary edema in COVID-19 patients. In fact, the so called Bradykinin Storm is likely responsible for most of the observed COVID-19 symptoms.\nInflammation plays a fundamental role in the pathogenesis and progression of COVID-19, ranging from common colds to fatal cases of pneumonia due to the cytokine release syndrome (CRS) that affected patients, determining the severe conditions. In COVID-19 the homeostatic equilibrium between TREG cells (IL-10) and Th17 cells (IL-17) is broken: inflammatory cytokine levels (IL-1, TNF) are elevated in the lungs of COVID-19 patients, resulting in an increase in HA-synthase-2 (HAS2) in alveolar epithelial cells CD31+, EpCAM+ and fibroblasts. The imbalance between pro-inflammatory and anti-inflammatory cytokines, leads to the CRS, an excessive and damaging host inflammation [28]. As a consequence of CRS [29], due to a severe infection of SARS-CoV-2 of the respiratory epithelium, the ARDS was observed in COVID-19 [30]. Edema and an IL-1β mediated proinflammatory response were increased in the lung parenchyma. Macrophages and dendritic cells produce IL-1β through macro-molecular complexes called inflammasomes, including the major element present in the pulmonary tissue and the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome [20]. Following a precise stimulus, the activation and recruitment domain of caspase (ASC) and the catalytically inactive procaspase-1 assemble, the procaspase-1 turns into active caspase-1, the inactive pro-IL-1β matures in IL-1β and the NLRP3 inflammasome is activated. The NLRP3 inflammasomes and IL-1β driven proinflammatory cascades correlate with worsening of several respiratory diseases, including COVID-19.\nPatients affected by obesity showed a severe consequence of COVID-19 [31], due to the high concentrations of TNF-α, MCP-1 and IL-6 produced in the meantime by visceral and subcutaneous adipose tissue and by innate immunity [32]. Moreover, leptin, released by adipose tissue, helps to increase inflammatory milieu with a dysregulation of the immune response [33].\nThis umbrella review seeks to answer the question of whether a nutritional approach can be used to enhance the immune system’s response to obesity in obese patients affected by COVID-19.\nImmunonutrition has been based on the concept that malnutrition impairs immune function, used to modify inflammatory or immune responses. This concept may be applied to any situation in which a supply of specific nutrients is necessary to modify inflammatory or immune responses. Immunonutrients can promote patient recovery by inhibiting inflammatory responses and regulating immune function. Therefore, immunonutrition involves feeding enriched with various pharmaconutrients (arginine, glutamine, omega-3-fatty acids, ribonucleotides and certain trace elements and antioxidants compound, vitamins and minerals) to modulate inflammatory responses, the acquired immune response, and to improve patient outcomes [34].\nPersonalized immunonutrition for patients with obesity should be the first therapeutic choice to reduce the risk of infections and the disease course in COVID-19 patients. That therapeutic strategy could be effective in case of other potential epidemic infections. It would also allow a reduction of the enormous medical care cost supported by the National Health Service."}

{"project":"LitCovid-PubTator","denotations":[{"id":"122","span":{"begin":15,"end":27},"obj":"Disease"},{"id":"123","span":{"begin":32,"end":40},"obj":"Disease"},{"id":"135","span":{"begin":2075,"end":2090},"obj":"Gene"},{"id":"136","span":{"begin":2092,"end":2095},"obj":"Gene"},{"id":"137","span":{"begin":2153,"end":2156},"obj":"Gene"},{"id":"138","span":{"begin":2439,"end":2442},"obj":"Gene"},{"id":"139","span":{"begin":72,"end":77},"obj":"Species"},{"id":"140","span":{"begin":233,"end":238},"obj":"Species"},{"id":"141","span":{"begin":1250,"end":1258},"obj":"Gene"},{"id":"142","span":{"begin":88,"end":98},"obj":"Disease"},{"id":"143","span":{"begin":1236,"end":1248},"obj":"Disease"},{"id":"144","span":{"begin":2230,"end":2233},"obj":"Disease"},{"id":"145","span":{"begin":2289,"end":2292},"obj":"Disease"},{"id":"147","span":{"begin":2529,"end":2532},"obj":"Gene"},{"id":"159","span":{"begin":2743,"end":2761},"obj":"Gene"},{"id":"160","span":{"begin":2946,"end":2949},"obj":"Gene"},{"id":"161","span":{"begin":2999,"end":3003},"obj":"Gene"},{"id":"162","span":{"begin":3097,"end":3102},"obj":"Gene"},{"id":"163","span":{"begin":3104,"end":3109},"obj":"Gene"},{"id":"164","span":{"begin":3111,"end":3115},"obj":"Gene"},{"id":"165","span":{"begin":3120,"end":3124},"obj":"Gene"},{"id":"166","span":{"begin":3185,"end":3190},"obj":"Gene"},{"id":"167","span":{"begin":3195,"end":3200},"obj":"Gene"},{"id":"168","span":{"begin":2934,"end":2944},"obj":"Gene"},{"id":"169","span":{"begin":2707,"end":2710},"obj":"Disease"},{"id":"176","span":{"begin":6079,"end":6082},"obj":"Gene"},{"id":"177","span":{"begin":5765,"end":5783},"obj":"Species"},{"id":"178","span":{"begin":5932,"end":5936},"obj":"Gene"},{"id":"179","span":{"begin":5846,"end":5856},"obj":"Gene"},{"id":"180","span":{"begin":5841,"end":5844},"obj":"Gene"},{"id":"181","span":{"begin":6084,"end":6099},"obj":"Disease"},{"id":"219","span":{"begin":3575,"end":3580},"obj":"Gene"},{"id":"220","span":{"begin":3691,"end":3698},"obj":"Gene"},{"id":"221","span":{"begin":3700,"end":3706},"obj":"Gene"},{"id":"222","span":{"begin":3715,"end":3719},"obj":"Gene"},{"id":"223","span":{"begin":3721,"end":3725},"obj":"Gene"},{"id":"224","span":{"begin":3727,"end":3731},"obj":"Gene"},{"id":"225","span":{"begin":3733,"end":3737},"obj":"Gene"},{"id":"226","span":{"begin":3739,"end":3744},"obj":"Gene"},{"id":"227","span":{"begin":3746,"end":3751},"obj":"Gene"},{"id":"228","span":{"begin":3760,"end":3765},"obj":"Gene"},{"id":"229","span":{"begin":3767,"end":3772},"obj":"Gene"},{"id":"230","span":{"begin":3774,"end":3779},"obj":"Gene"},{"id":"231","span":{"begin":3781,"end":3786},"obj":"Gene"},{"id":"232","span":{"begin":3791,"end":3796},"obj":"Gene"},{"id":"233","span":{"begin":3843,"end":3874},"obj":"Gene"},{"id":"234","span":{"begin":3876,"end":3883},"obj":"Gene"},{"id":"235","span":{"begin":3962,"end":3968},"obj":"Gene"},{"id":"236","span":{"begin":3970,"end":4000},"obj":"Gene"},{"id":"237","span":{"begin":4002,"end":4007},"obj":"Gene"},{"id":"238","span":{"begin":4010,"end":4044},"obj":"Gene"},{"id":"239","span":{"begin":4046,"end":4051},"obj":"Gene"},{"id":"240","span":{"begin":4059,"end":4064},"obj":"Gene"},{"id":"241","span":{"begin":4318,"end":4322},"obj":"Gene"},{"id":"242","span":{"begin":4325,"end":4329},"obj":"Gene"},{"id":"243","span":{"begin":4490,"end":4512},"obj":"Gene"},{"id":"244","span":{"begin":4514,"end":4517},"obj":"Gene"},{"id":"245","span":{"begin":4536,"end":4541},"obj":"Gene"},{"id":"246","span":{"begin":4547,"end":4551},"obj":"Gene"},{"id":"247","span":{"begin":5418,"end":5422},"obj":"Gene"},{"id":"248","span":{"begin":5540,"end":5545},"obj":"Gene"},{"id":"249","span":{"begin":5547,"end":5594},"obj":"Gene"},{"id":"250","span":{"begin":5258,"end":5271},"obj":"Species"},{"id":"251","span":{"begin":5353,"end":5364},"obj":"Species"},{"id":"252","span":{"begin":5474,"end":5481},"obj":"Chemical"},{"id":"253","span":{"begin":3609,"end":3625},"obj":"Disease"},{"id":"254","span":{"begin":4473,"end":4485},"obj":"Disease"},{"id":"255","span":{"begin":4679,"end":4691},"obj":"Disease"},{"id":"261","span":{"begin":6309,"end":6313},"obj":"Gene"},{"id":"262","span":{"begin":6315,"end":6320},"obj":"Gene"},{"id":"263","span":{"begin":6322,"end":6327},"obj":"Gene"},{"id":"264","span":{"begin":6114,"end":6126},"obj":"Disease"},{"id":"265","span":{"begin":6344,"end":6356},"obj":"Disease"},{"id":"271","span":{"begin":6563,"end":6569},"obj":"Gene"},{"id":"272","span":{"begin":6587,"end":6592},"obj":"Gene"},{"id":"273","span":{"begin":6721,"end":6740},"obj":"Species"},{"id":"274","span":{"begin":6742,"end":6752},"obj":"Species"},{"id":"275","span":{"begin":6693,"end":6709},"obj":"Disease"},{"id":"279","span":{"begin":6944,"end":6952},"obj":"Gene"},{"id":"280","span":{"begin":6760,"end":6770},"obj":"Species"},{"id":"281","span":{"begin":6827,"end":6840},"obj":"Species"},{"id":"323","span":{"begin":7127,"end":7158},"obj":"Gene"},{"id":"324","span":{"begin":7160,"end":7164},"obj":"Gene"},{"id":"325","span":{"begin":7209,"end":7213},"obj":"Gene"},{"id":"326","span":{"begin":7469,"end":7473},"obj":"Gene"},{"id":"327","span":{"begin":7524,"end":7527},"obj":"Gene"},{"id":"328","span":{"begin":7616,"end":7620},"obj":"Gene"},{"id":"329","span":{"begin":7802,"end":7806},"obj":"Gene"},{"id":"330","span":{"begin":8619,"end":8623},"obj":"Gene"},{"id":"331","span":{"begin":8690,"end":8694},"obj":"Gene"},{"id":"332","span":{"begin":8721,"end":8731},"obj":"Gene"},{"id":"333","span":{"begin":8793,"end":8799},"obj":"Gene"},{"id":"334","span":{"begin":8911,"end":8922},"obj":"Gene"},{"id":"335","span":{"begin":8980,"end":8990},"obj":"Gene"},{"id":"336","span":{"begin":8992,"end":8995},"obj":"Gene"},{"id":"337","span":{"begin":8998,"end":9001},"obj":"Gene"},{"id":"338","span":{"begin":9095,"end":9105},"obj":"Gene"},{"id":"339","span":{"begin":9265,"end":9271},"obj":"Gene"},{"id":"340","span":{"begin":9282,"end":9285},"obj":"Gene"},{"id":"341","span":{"begin":7786,"end":7787},"obj":"Gene"},{"id":"342","span":{"begin":7383,"end":7391},"obj":"Gene"},{"id":"343","span":{"begin":7036,"end":7046},"obj":"Species"},{"id":"344","span":{"begin":7172,"end":7180},"obj":"Species"},{"id":"345","span":{"begin":7336,"end":7346},"obj":"Species"},{"id":"346","span":{"begin":7768,"end":7777},"obj":"Species"},{"id":"347","span":{"begin":8659,"end":8669},"obj":"Species"},{"id":"348","span":{"begin":9079,"end":9085},"obj":"Chemical"},{"id":"349","span":{"begin":7419,"end":7427},"obj":"Disease"},{"id":"350","span":{"begin":7555,"end":7590},"obj":"Disease"},{"id":"351","span":{"begin":7592,"end":7596},"obj":"Disease"},{"id":"352","span":{"begin":7698,"end":7707},"obj":"Disease"},{"id":"353","span":{"begin":7712,"end":7735},"obj":"Disease"},{"id":"354","span":{"begin":7748,"end":7756},"obj":"Disease"},{"id":"355","span":{"begin":7901,"end":7913},"obj":"Disease"},{"id":"356","span":{"begin":7959,"end":7974},"obj":"Disease"},{"id":"357","span":{"begin":8031,"end":8039},"obj":"Disease"},{"id":"358","span":{"begin":8371,"end":8378},"obj":"Disease"},{"id":"359","span":{"begin":8380,"end":8403},"obj":"Disease"},{"id":"360","span":{"begin":8405,"end":8413},"obj":"Disease"},{"id":"361","span":{"begin":8415,"end":8441},"obj":"Disease"},{"id":"362","span":{"begin":8446,"end":8452},"obj":"Disease"},{"id":"363","span":{"begin":9230,"end":9241},"obj":"Disease"},{"id":"373","span":{"begin":9442,"end":9445},"obj":"Gene"},{"id":"374","span":{"begin":9485,"end":9488},"obj":"Gene"},{"id":"375","span":{"begin":9538,"end":9541},"obj":"Gene"},{"id":"376","span":{"begin":9673,"end":9679},"obj":"Gene"},{"id":"377","span":{"begin":9412,"end":9415},"obj":"Gene"},{"id":"378","span":{"begin":9569,"end":9572},"obj":"Gene"},{"id":"379","span":{"begin":9551,"end":9567},"obj":"Disease"},{"id":"380","span":{"begin":9619,"end":9625},"obj":"Disease"},{"id":"381","span":{"begin":9645,"end":9649},"obj":"Disease"},{"id":"394","span":{"begin":9852,"end":9856},"obj":"Gene"},{"id":"395","span":{"begin":9909,"end":9919},"obj":"Gene"},{"id":"396","span":{"begin":9998,"end":10008},"obj":"Gene"},{"id":"397","span":{"begin":10186,"end":10196},"obj":"Gene"},{"id":"398","span":{"begin":10153,"end":10161},"obj":"Species"},{"id":"399","span":{"begin":10059,"end":10070},"obj":"Chemical"},{"id":"400","span":{"begin":9786,"end":9795},"obj":"Disease"},{"id":"401","span":{"begin":9949,"end":9959},"obj":"Disease"},{"id":"402","span":{"begin":9989,"end":9994},"obj":"Disease"},{"id":"403","span":{"begin":10125,"end":10140},"obj":"Disease"},{"id":"404","span":{"begin":10144,"end":10152},"obj":"Disease"},{"id":"405","span":{"begin":10250,"end":10258},"obj":"Disease"},{"id":"443","span":{"begin":10572,"end":10577},"obj":"Gene"},{"id":"444","span":{"begin":10595,"end":10600},"obj":"Gene"},{"id":"445","span":{"begin":10643,"end":10647},"obj":"Gene"},{"id":"446","span":{"begin":10649,"end":10652},"obj":"Gene"},{"id":"447","span":{"begin":10730,"end":10743},"obj":"Gene"},{"id":"448","span":{"begin":10745,"end":10749},"obj":"Gene"},{"id":"449","span":{"begin":10780,"end":10784},"obj":"Gene"},{"id":"450","span":{"begin":10787,"end":10792},"obj":"Gene"},{"id":"451","span":{"begin":11105,"end":11110},"obj":"Gene"},{"id":"452","span":{"begin":11224,"end":11229},"obj":"Gene"},{"id":"453","span":{"begin":11451,"end":11456},"obj":"Gene"},{"id":"454","span":{"begin":11548,"end":11555},"obj":"Gene"},{"id":"455","span":{"begin":11557,"end":11560},"obj":"Gene"},{"id":"456","span":{"begin":11651,"end":11660},"obj":"Gene"},{"id":"457","span":{"begin":11675,"end":11684},"obj":"Gene"},{"id":"458","span":{"begin":11696,"end":11701},"obj":"Gene"},{"id":"459","span":{"begin":11710,"end":11715},"obj":"Gene"},{"id":"460","span":{"begin":11747,"end":11752},"obj":"Gene"},{"id":"461","span":{"begin":11771,"end":11776},"obj":"Gene"},{"id":"462","span":{"begin":10971,"end":10974},"obj":"Gene"},{"id":"463","span":{"begin":10896,"end":10899},"obj":"Gene"},{"id":"464","span":{"begin":10448,"end":10451},"obj":"Gene"},{"id":"465","span":{"begin":10467,"end":10475},"obj":"Species"},{"id":"466","span":{"begin":10692,"end":10700},"obj":"Species"},{"id":"467","span":{"begin":11010,"end":11020},"obj":"Species"},{"id":"468","span":{"begin":10269,"end":10281},"obj":"Disease"},{"id":"469","span":{"begin":10346,"end":10354},"obj":"Disease"},{"id":"470","span":{"begin":10400,"end":10409},"obj":"Disease"},{"id":"471","span":{"begin":10515,"end":10523},"obj":"Disease"},{"id":"472","span":{"begin":10683,"end":10691},"obj":"Disease"},{"id":"473","span":{"begin":10932,"end":10944},"obj":"Disease"},{"id":"474","span":{"begin":10997,"end":11006},"obj":"Disease"},{"id":"475","span":{"begin":11056,"end":11060},"obj":"Disease"},{"id":"476","span":{"begin":11077,"end":11085},"obj":"Disease"},{"id":"477","span":{"begin":11092,"end":11097},"obj":"Disease"},{"id":"478","span":{"begin":11845,"end":11865},"obj":"Disease"},{"id":"479","span":{"begin":11877,"end":11885},"obj":"Disease"},{"id":"487","span":{"begin":11996,"end":12001},"obj":"Gene"},{"id":"488","span":{"begin":12003,"end":12008},"obj":"Gene"},{"id":"489","span":{"begin":12013,"end":12017},"obj":"Gene"},{"id":"490","span":{"begin":12126,"end":12132},"obj":"Gene"},{"id":"491","span":{"begin":11887,"end":11895},"obj":"Species"},{"id":"492","span":{"begin":11908,"end":11915},"obj":"Disease"},{"id":"493","span":{"begin":11947,"end":11955},"obj":"Disease"},{"id":"498","span":{"begin":12406,"end":12414},"obj":"Species"},{"id":"499","span":{"begin":12389,"end":12396},"obj":"Disease"},{"id":"500","span":{"begin":12400,"end":12405},"obj":"Disease"},{"id":"501","span":{"begin":12427,"end":12435},"obj":"Disease"},{"id":"509","span":{"begin":12745,"end":12752},"obj":"Species"},{"id":"510","span":{"begin":13132,"end":13139},"obj":"Species"},{"id":"511","span":{"begin":12916,"end":12924},"obj":"Chemical"},{"id":"512","span":{"begin":12926,"end":12935},"obj":"Chemical"},{"id":"513","span":{"begin":12937,"end":12956},"obj":"Chemical"},{"id":"514","span":{"begin":12958,"end":12973},"obj":"Chemical"},{"id":"515","span":{"begin":12488,"end":12508},"obj":"Disease"},{"id":"522","span":{"begin":13188,"end":13196},"obj":"Species"},{"id":"523","span":{"begin":13317,"end":13325},"obj":"Species"},{"id":"524","span":{"begin":13202,"end":13209},"obj":"Disease"},{"id":"525","span":{"begin":13271,"end":13281},"obj":"Disease"},{"id":"526","span":{"begin":13308,"end":13316},"obj":"Disease"},{"id":"527","span":{"begin":13408,"end":13418},"obj":"Disease"}],"attributes":[{"id":"A122","pred":"tao:has_database_id","subj":"122","obj":"MESH:D007249"},{"id":"A123","pred":"tao:has_database_id","subj":"123","obj":"MESH:C000657245"},{"id":"A135","pred":"tao:has_database_id","subj":"135","obj":"Gene:6962"},{"id":"A136","pred":"tao:has_database_id","subj":"136","obj":"Gene:6962"},{"id":"A137","pred":"tao:has_database_id","subj":"137","obj":"Gene:6962"},{"id":"A138","pred":"tao:has_database_id","subj":"138","obj":"Gene:6962"},{"id":"A139","pred":"tao:has_database_id","subj":"139","obj":"Tax:9606"},{"id":"A140","pred":"tao:has_database_id","subj":"140","obj":"Tax:9606"},{"id":"A141","pred":"tao:has_database_id","subj":"141","obj":"Gene:43740571"},{"id":"A142","pred":"tao:has_database_id","subj":"142","obj":"MESH:D007239"},{"id":"A143","pred":"tao:has_database_id","subj":"143","obj":"MESH:D007249"},{"id":"A144","pred":"tao:has_database_id","subj":"144","obj":"MESH:D011125"},{"id":"A145","pred":"tao:has_database_id","subj":"145","obj":"MESH:D011125"},{"id":"A147","pred":"tao:has_database_id","subj":"147","obj":"Gene:920"},{"id":"A159","pred":"tao:has_database_id","subj":"159","obj":"Gene:3558"},{"id":"A160","pred":"tao:has_database_id","subj":"160","obj":"Gene:3439"},{"id":"A161","pred":"tao:has_database_id","subj":"161","obj":"Gene:3565"},{"id":"A162","pred":"tao:has_database_id","subj":"162","obj":"Gene:3553"},{"id":"A163","pred":"tao:has_database_id","subj":"163","obj":"Gene:51561"},{"id":"A164","pred":"tao:has_database_id","subj":"164","obj":"Gene:7039"},{"id":"A165","pred":"tao:has_database_id","subj":"165","obj":"Gene:3569"},{"id":"A166","pred":"tao:has_database_id","subj":"166","obj":"Gene:3605"},{"id":"A167","pred":"tao:has_database_id","subj":"167","obj":"Gene:50616"},{"id":"A168","pred":"tao:has_database_id","subj":"168","obj":"Gene:3439"},{"id":"A169","pred":"tao:has_database_id","subj":"169","obj":"MESH:D011125"},{"id":"A176","pred":"tao:has_database_id","subj":"176","obj":"Gene:7124"},{"id":"A177","pred":"tao:has_database_id","subj":"177","obj":"Tax:2697049"},{"id":"A178","pred":"tao:has_database_id","subj":"178","obj":"Gene:4790"},{"id":"A179","pred":"tao:has_database_id","subj":"179","obj":"Gene:3439"},{"id":"A180","pred":"tao:has_database_id","subj":"180","obj":"Gene:3439"},{"id":"A181","pred":"tao:has_database_id","subj":"181","obj":"MESH:D009336"},{"id":"A219","pred":"tao:has_database_id","subj":"219","obj":"Gene:6772"},{"id":"A220","pred":"tao:has_database_id","subj":"220","obj":"Gene:3440"},{"id":"A221","pred":"tao:has_database_id","subj":"221","obj":"Gene:3458"},{"id":"A222","pred":"tao:has_database_id","subj":"222","obj":"Gene:3558"},{"id":"A223","pred":"tao:has_database_id","subj":"223","obj":"Gene:3562"},{"id":"A224","pred":"tao:has_database_id","subj":"224","obj":"Gene:3569"},{"id":"A225","pred":"tao:has_database_id","subj":"225","obj":"Gene:3578"},{"id":"A226","pred":"tao:has_database_id","subj":"226","obj":"Gene:3586"},{"id":"A227","pred":"tao:has_database_id","subj":"227","obj":"Gene:3589"},{"id":"A228","pred":"tao:has_database_id","subj":"228","obj":"Gene:3600"},{"id":"A229","pred":"tao:has_database_id","subj":"229","obj":"Gene:59067"},{"id":"A230","pred":"tao:has_database_id","subj":"230","obj":"Gene:50616"},{"id":"A231","pred":"tao:has_database_id","subj":"231","obj":"Gene:55801"},{"id":"A232","pred":"tao:has_database_id","subj":"232","obj":"Gene:246778"},{"id":"A233","pred":"tao:has_database_id","subj":"233","obj":"Gene:3627"},{"id":"A234","pred":"tao:has_database_id","subj":"234","obj":"Gene:3627"},{"id":"A235","pred":"tao:has_database_id","subj":"235","obj":"Gene:6352"},{"id":"A236","pred":"tao:has_database_id","subj":"236","obj":"Gene:6352"},{"id":"A237","pred":"tao:has_database_id","subj":"237","obj":"Gene:6352"},{"id":"A238","pred":"tao:has_database_id","subj":"238","obj":"Gene:6347"},{"id":"A239","pred":"tao:has_database_id","subj":"239","obj":"Gene:6347"},{"id":"A240","pred":"tao:has_database_id","subj":"240","obj":"Gene:3458"},{"id":"A241","pred":"tao:has_database_id","subj":"241","obj":"Gene:4790"},{"id":"A242","pred":"tao:has_database_id","subj":"242","obj":"Gene:4790"},{"id":"A243","pred":"tao:has_database_id","subj":"243","obj":"Gene:7124"},{"id":"A244","pred":"tao:has_database_id","subj":"244","obj":"Gene:7124"},{"id":"A245","pred":"tao:has_database_id","subj":"245","obj":"Gene:3552"},{"id":"A246","pred":"tao:has_database_id","subj":"246","obj":"Gene:3569"},{"id":"A247","pred":"tao:has_database_id","subj":"247","obj":"Gene:4790"},{"id":"A248","pred":"tao:has_database_id","subj":"248","obj":"Gene:114548"},{"id":"A249","pred":"tao:has_database_id","subj":"249","obj":"Gene:114548"},{"id":"A250","pred":"tao:has_database_id","subj":"250","obj":"Tax:11118"},{"id":"A251","pred":"tao:has_database_id","subj":"251","obj":"Tax:11118"},{"id":"A252","pred":"tao:has_database_id","subj":"252","obj":"MESH:D007930"},{"id":"A253","pred":"tao:has_database_id","subj":"253","obj":"MESH:D001102"},{"id":"A254","pred":"tao:has_database_id","subj":"254","obj":"MESH:D007249"},{"id":"A255","pred":"tao:has_database_id","subj":"255","obj":"MESH:D007249"},{"id":"A261","pred":"tao:has_database_id","subj":"261","obj":"Gene:3552"},{"id":"A262","pred":"tao:has_database_id","subj":"262","obj":"Gene:3586"},{"id":"A263","pred":"tao:has_database_id","subj":"263","obj":"Gene:3596"},{"id":"A264","pred":"tao:has_database_id","subj":"264","obj":"MESH:D007249"},{"id":"A265","pred":"tao:has_database_id","subj":"265","obj":"MESH:D007249"},{"id":"A271","pred":"tao:has_database_id","subj":"271","obj":"Gene:3586"},{"id":"A272","pred":"tao:has_database_id","subj":"272","obj":"Gene:3605"},{"id":"A273","pred":"tao:has_database_id","subj":"273","obj":"Tax:2697049"},{"id":"A274","pred":"tao:has_database_id","subj":"274","obj":"Tax:2697049"},{"id":"A275","pred":"tao:has_database_id","subj":"275","obj":"MESH:D001102"},{"id":"A279","pred":"tao:has_database_id","subj":"279","obj":"Gene:43740571"},{"id":"A280","pred":"tao:has_database_id","subj":"280","obj":"Tax:2697049"},{"id":"A281","pred":"tao:has_database_id","subj":"281","obj":"Tax:11118"},{"id":"A323","pred":"tao:has_database_id","subj":"323","obj":"Gene:59272"},{"id":"A324","pred":"tao:has_database_id","subj":"324","obj":"Gene:59272"},{"id":"A325","pred":"tao:has_database_id","subj":"325","obj":"Gene:59272"},{"id":"A326","pred":"tao:has_database_id","subj":"326","obj":"Gene:59272"},{"id":"A327","pred":"tao:has_database_id","subj":"327","obj":"Gene:283"},{"id":"A328","pred":"tao:has_database_id","subj":"328","obj":"Gene:59272"},{"id":"A329","pred":"tao:has_database_id","subj":"329","obj":"Gene:4790"},{"id":"A330","pred":"tao:has_database_id","subj":"330","obj":"Gene:59272"},{"id":"A331","pred":"tao:has_database_id","subj":"331","obj":"Gene:59272"},{"id":"A332","pred":"tao:has_database_id","subj":"332","obj":"Gene:3827"},{"id":"A333","pred":"tao:has_database_id","subj":"333","obj":"Gene:623"},{"id":"A334","pred":"tao:has_database_id","subj":"334","obj":"Gene:624"},{"id":"A335","pred":"tao:has_database_id","subj":"335","obj":"Gene:3827"},{"id":"A336","pred":"tao:has_database_id","subj":"336","obj":"Gene:3827"},{"id":"A337","pred":"tao:has_database_id","subj":"337","obj":"Gene:3827"},{"id":"A338","pred":"tao:has_database_id","subj":"338","obj":"Gene:9622"},{"id":"A339","pred":"tao:has_database_id","subj":"339","obj":"Gene:624"},{"id":"A340","pred":"tao:has_database_id","subj":"340","obj":"Gene:3827"},{"id":"A341","pred":"tao:has_database_id","subj":"341","obj":"Gene:43740570"},{"id":"A342","pred":"tao:has_database_id","subj":"342","obj":"Gene:43740571"},{"id":"A343","pred":"tao:has_database_id","subj":"343","obj":"Tax:2697049"},{"id":"A344","pred":"tao:has_database_id","subj":"344","obj":"Tax:694009"},{"id":"A345","pred":"tao:has_database_id","subj":"345","obj":"Tax:2697049"},{"id":"A346","pred":"tao:has_database_id","subj":"346","obj":"Tax:2697049"},{"id":"A347","pred":"tao:has_database_id","subj":"347","obj":"Tax:2697049"},{"id":"A348","pred":"tao:has_database_id","subj":"348","obj":"MESH:D012694"},{"id":"A349","pred":"tao:has_database_id","subj":"349","obj":"MESH:D007239"},{"id":"A350","pred":"tao:has_database_id","subj":"350","obj":"MESH:D012128"},{"id":"A351","pred":"tao:has_database_id","subj":"351","obj":"MESH:D012128"},{"id":"A352","pred":"tao:has_database_id","subj":"352","obj":"MESH:D003967"},{"id":"A353","pred":"tao:has_database_id","subj":"353","obj":"MESH:D007249"},{"id":"A354","pred":"tao:has_database_id","subj":"354","obj":"MESH:C000657245"},{"id":"A355","pred":"tao:has_database_id","subj":"355","obj":"MESH:D007249"},{"id":"A356","pred":"tao:has_database_id","subj":"356","obj":"MESH:C000657245"},{"id":"A357","pred":"tao:has_database_id","subj":"357","obj":"MESH:C000657245"},{"id":"A358","pred":"tao:has_database_id","subj":"358","obj":"MESH:D009765"},{"id":"A359","pred":"tao:has_database_id","subj":"359","obj":"MESH:D002318"},{"id":"A360","pred":"tao:has_database_id","subj":"360","obj":"MESH:D003920"},{"id":"A361","pred":"tao:has_database_id","subj":"361","obj":"MESH:D019636"},{"id":"A362","pred":"tao:has_database_id","subj":"362","obj":"MESH:D009369"},{"id":"A363","pred":"tao:has_database_id","subj":"363","obj":"MESH:D007022"},{"id":"A373","pred":"tao:has_database_id","subj":"373","obj":"Gene:3827"},{"id":"A374","pred":"tao:has_database_id","subj":"374","obj":"Gene:1636"},{"id":"A375","pred":"tao:has_database_id","subj":"375","obj":"Gene:3827"},{"id":"A376","pred":"tao:has_database_id","subj":"376","obj":"Gene:623"},{"id":"A377","pred":"tao:has_database_id","subj":"377","obj":"Gene:1636"},{"id":"A378","pred":"tao:has_database_id","subj":"378","obj":"Gene:3827"},{"id":"A379","pred":"tao:has_database_id","subj":"379","obj":"MESH:D007022"},{"id":"A380","pred":"tao:has_database_id","subj":"380","obj":"MESH:D014947"},{"id":"A381","pred":"tao:has_database_id","subj":"381","obj":"MESH:D010146"},{"id":"A394","pred":"tao:has_database_id","subj":"394","obj":"Gene:59272"},{"id":"A395","pred":"tao:has_database_id","subj":"395","obj":"Gene:9622"},{"id":"A396","pred":"tao:has_database_id","subj":"396","obj":"Gene:3827"},{"id":"A397","pred":"tao:has_database_id","subj":"397","obj":"Gene:3827"},{"id":"A398","pred":"tao:has_database_id","subj":"398","obj":"Tax:9606"},{"id":"A399","pred":"tao:has_database_id","subj":"399","obj":"MESH:D004837"},{"id":"A400","pred":"tao:has_database_id","subj":"400","obj":"MESH:D007239"},{"id":"A401","pred":"tao:has_database_id","subj":"401","obj":"MESH:D000799"},{"id":"A402","pred":"tao:has_database_id","subj":"402","obj":"MESH:D004487"},{"id":"A403","pred":"tao:has_database_id","subj":"403","obj":"MESH:D011654"},{"id":"A404","pred":"tao:has_database_id","subj":"404","obj":"MESH:C000657245"},{"id":"A405","pred":"tao:has_database_id","subj":"405","obj":"MESH:C000657245"},{"id":"A443","pred":"tao:has_database_id","subj":"443","obj":"Gene:3586"},{"id":"A444","pred":"tao:has_database_id","subj":"444","obj":"Gene:3605"},{"id":"A445","pred":"tao:has_database_id","subj":"445","obj":"Gene:3552"},{"id":"A446","pred":"tao:has_database_id","subj":"446","obj":"Gene:7124"},{"id":"A447","pred":"tao:has_database_id","subj":"447","obj":"Gene:3037"},{"id":"A448","pred":"tao:has_database_id","subj":"448","obj":"Gene:3037"},{"id":"A449","pred":"tao:has_database_id","subj":"449","obj":"Gene:5175"},{"id":"A450","pred":"tao:has_database_id","subj":"450","obj":"Gene:4072"},{"id":"A451","pred":"tao:has_database_id","subj":"451","obj":"Gene:3552"},{"id":"A452","pred":"tao:has_database_id","subj":"452","obj":"Gene:3552"},{"id":"A453","pred":"tao:has_database_id","subj":"453","obj":"Gene:114548"},{"id":"A454","pred":"tao:has_database_id","subj":"454","obj":"Gene:834"},{"id":"A455","pred":"tao:has_database_id","subj":"455","obj":"Gene:29108"},{"id":"A456","pred":"tao:has_database_id","subj":"456","obj":"Gene:834"},{"id":"A457","pred":"tao:has_database_id","subj":"457","obj":"Gene:3553"},{"id":"A458","pred":"tao:has_database_id","subj":"458","obj":"Gene:3552"},{"id":"A459","pred":"tao:has_database_id","subj":"459","obj":"Gene:114548"},{"id":"A460","pred":"tao:has_database_id","subj":"460","obj":"Gene:114548"},{"id":"A461","pred":"tao:has_database_id","subj":"461","obj":"Gene:3552"},{"id":"A462","pred":"tao:has_database_id","subj":"462","obj":"Gene:7291"},{"id":"A463","pred":"tao:has_database_id","subj":"463","obj":"Gene:7291"},{"id":"A464","pred":"tao:has_database_id","subj":"464","obj":"Gene:7291"},{"id":"A465","pred":"tao:has_database_id","subj":"465","obj":"Tax:9606"},{"id":"A466","pred":"tao:has_database_id","subj":"466","obj":"Tax:9606"},{"id":"A467","pred":"tao:has_database_id","subj":"467","obj":"Tax:2697049"},{"id":"A468","pred":"tao:has_database_id","subj":"468","obj":"MESH:D007249"},{"id":"A469","pred":"tao:has_database_id","subj":"469","obj":"MESH:C000657245"},{"id":"A470","pred":"tao:has_database_id","subj":"470","obj":"MESH:D011014"},{"id":"A471","pred":"tao:has_database_id","subj":"471","obj":"MESH:C000657245"},{"id":"A472","pred":"tao:has_database_id","subj":"472","obj":"MESH:C000657245"},{"id":"A473","pred":"tao:has_database_id","subj":"473","obj":"MESH:D007249"},{"id":"A474","pred":"tao:has_database_id","subj":"474","obj":"MESH:D007239"},{"id":"A475","pred":"tao:has_database_id","subj":"475","obj":"MESH:D012128"},{"id":"A476","pred":"tao:has_database_id","subj":"476","obj":"MESH:C000657245"},{"id":"A477","pred":"tao:has_database_id","subj":"477","obj":"MESH:D004487"},{"id":"A478","pred":"tao:has_database_id","subj":"478","obj":"MESH:D012140"},{"id":"A479","pred":"tao:has_database_id","subj":"479","obj":"MESH:C000657245"},{"id":"A487","pred":"tao:has_database_id","subj":"487","obj":"Gene:7124"},{"id":"A488","pred":"tao:has_database_id","subj":"488","obj":"Gene:6347"},{"id":"A489","pred":"tao:has_database_id","subj":"489","obj":"Gene:3569"},{"id":"A490","pred":"tao:has_database_id","subj":"490","obj":"Gene:3952"},{"id":"A491","pred":"tao:has_database_id","subj":"491","obj":"Tax:9606"},{"id":"A492","pred":"tao:has_database_id","subj":"492","obj":"MESH:D009765"},{"id":"A493","pred":"tao:has_database_id","subj":"493","obj":"MESH:C000657245"},{"id":"A498","pred":"tao:has_database_id","subj":"498","obj":"Tax:9606"},{"id":"A499","pred":"tao:has_database_id","subj":"499","obj":"MESH:D009765"},{"id":"A500","pred":"tao:has_database_id","subj":"500","obj":"MESH:D009765"},{"id":"A501","pred":"tao:has_database_id","subj":"501","obj":"MESH:C000657245"},{"id":"A509","pred":"tao:has_database_id","subj":"509","obj":"Tax:9606"},{"id":"A510","pred":"tao:has_database_id","subj":"510","obj":"Tax:9606"},{"id":"A511","pred":"tao:has_database_id","subj":"511","obj":"MESH:D001120"},{"id":"A512","pred":"tao:has_database_id","subj":"512","obj":"MESH:D005973"},{"id":"A513","pred":"tao:has_database_id","subj":"513","obj":"MESH:D015525"},{"id":"A514","pred":"tao:has_database_id","subj":"514","obj":"MESH:D012265"},{"id":"A515","pred":"tao:has_database_id","subj":"515","obj":"MESH:D044342"},{"id":"A522","pred":"tao:has_database_id","subj":"522","obj":"Tax:9606"},{"id":"A523","pred":"tao:has_database_id","subj":"523","obj":"Tax:9606"},{"id":"A524","pred":"tao:has_database_id","subj":"524","obj":"MESH:D009765"},{"id":"A525","pred":"tao:has_database_id","subj":"525","obj":"MESH:D007239"},{"id":"A526","pred":"tao:has_database_id","subj":"526","obj":"MESH:C000657245"},{"id":"A527","pred":"tao:has_database_id","subj":"527","obj":"MESH:D007239"}],"namespaces":[{"prefix":"Tax","uri":"https://www.ncbi.nlm.nih.gov/taxonomy/"},{"prefix":"MESH","uri":"https://id.nlm.nih.gov/mesh/"},{"prefix":"Gene","uri":"https://www.ncbi.nlm.nih.gov/gene/"},{"prefix":"CVCL","uri":"https://web.expasy.org/cellosaurus/CVCL_"}],"text":"Immune system, inflammation and COVID-19\nThe immune system protects the human body from infections by a series of pathogen (bacteria, viruses, fungi, parasites) [5]. A self-tolerance system prevents the immune response from damaging human tissues. The immune system is always active, carrying out surveillance. The defense to first exposure to the pathogen is represented by two complementary and cooperating functional divisions, the innate immune and, on the other hand, the adaptive immune response, that represents a response based on previous exposure [6]. The innate immune system is represented by dendritic cells, macrophages and neutrophils, with phagocytic activity, and by eosinophils, mast cells and natural killer cells, which release specific soluble antimicrobial factors. The innate immune system includes physical barriers, represented by interconnected epithelial cells (e.g. tight junctions and cellular interactions mediated by cadherin), epithelial cilia and the mucus layer of the respiratory, gastrointestinal and genitourinary epithelium. Moreover, soluble proteins and small bioactive molecules such as complement proteins, defensins and ficolins 1-3, pro-inflammatory cytokines, chemokines, lipid mediators of inflammation, membrane-bound receptors and cytoplasmic proteins are part of the innate immune system. Both innate and adaptive immunity is mediated by leukocytes. Lymphocytes circulate between the blood system and the lymphatic system, passing through the peripheral lymphoid organs, which includes the spleen, tonsils, appendix, lymph nodes and gut-associated lymphoid tissue (GALT). From a common lymphoid progenitor, four major populations of mature lymphocytes are derived, that belong to the adaptive immune system: of B lymphocytes (B cells) and T lymphocytes (T cells), natural killer (NK) cells, and NK-T cells. T-cells can be further categorized to cytotoxic T-cells (TC cells), helper T-cells (Th) and suppressor T-cells. The specific antigenic receptors of the adaptive response are represented by genes that code for an intact T cell receptor (TCR) and immunoglobulin genes (B cell antigen receptor; Ig). TCR is capable of binding the antigen processed by antigen-presenting cells (APC). Dendritic cells represent the most powerful class of APC, and express molecules of the major histocompatibility complex (MHC) of class I and II, necessary for the recognition of the antigen processed by TCR on T cells [7].\nFollowing the presentation of viral antigens via MHC II, the T helper CD4+ lymphocytes are activated and switch to the T helper 1 phenotype [8].\nThe activated T helper lymphocytes proliferate and release cytokines: after stimulation by antigen and APC, the Th0 cells begin to produce interleukin (IL)-2. Meanwhile, Th cells differentiate into Th1, Th2 and Th17 according to the nature of the cytokines present in the activation site: IL-12 produced by macrophages and type I Interferon (IFN) or NK cells induce differentiation towards Th1, IL-4 produced by NK1.1 + T cells, basophils or mast cells induce differentiation towards Th2, and IL-1b, IL-23, TGFβ and IL-6 induce differentiation towards Th17 [9]. Th17 cells produce IL-17 and IL-22, and antigen-induced Treg (iTreg).\nThe binding of the cytokine to its transmembrane cell surface receptor activates an intracellular signal transduction pathway, generally a Janus kinase (Jak), which, via a kinase cascade, phosphorylates its transcription protein (STAT). Phosphorylated STAT dimers and moves to the nucleus, initiating a new gene transcription. Mutation of STAT1 increases susceptibility to virus infections because it is involved in various signalling pathways, including IFN-α/β, IFN- γ, IFN-l, IL-2, IL-3, IL-6, IL-9, IL-10, IL-11, IL-12, IL-15, IL-21, IL-22, IL-26 and IL-27 [10], and chemokines of several types such as C-X-C motif chemokine ligand 10 (CXCL-10), Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted (RANTES)/Chemokine (C–C motif) ligand 5 (CCL-5), Monocyte Chemoattractant Protein-1 (MCP-1) [11]. IFN-γ promotes antigen-specific antibody production, increasing the activity of phagocytosis. In the meantime, PRRs trigger inflammatory signalling, with activation of transcription factors like nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). NFκB is the key transcriptional regulator of many pro-inflammatory cytokines, adhesion molecules, chemokines, growth factors and other mediators of inflammation, as tumour necrosis factor (TNF), interleukins 1 (IL-1β), 6 (IL-6), and 12 (IL-12), promotes cellular proliferation and protects against apoptosis providing a mechanism that determines chronic inflammation. The recognition of pathogens is achieved through the presence of pattern recognition receptors (PRRs) [12]. PRRs identify the microbe-associated molecular patterns (MAMPs), and defensive responses is activated. PRRs include Toll-like receptors (TLRs), that are able to recognize viral DNA, viral double-stranded RNA and viral single-stranded RNA. TLRs are expressed on macrophages, dendritic cells, neutrophils, eosinophils, epithelial cells and keratinocytes. In particular, intracellular TLR-7 and TLR-8 allow the innate recognition of the single-stranded RNA of coronaviruses [13]. Intracellular and extracellular PRRs recognized spike glycoprotein, of the coronavirus coat, starting the inflammatory process, through the NFκB pathway [14]. Moreover, Nucleotide-Binding Domain, Leucine-Rich Repeat (NLR) proteins have also been identified, and NALP3 (NACHT, LRR and PYD domains-containing protein 3) has a special function in the innate immune response [15]. The processes involved in antiviral immunity is shown in Fig. 1.\nFig. 1 Graphical representation of antiviral SARS-Coronavirus 2 immunity. B: B lymphocyte; CTL: cytotoxic; T lymphocyte; IFN: interferon; Ig: immunoglobulin; IL: interleukin; MHC: major histocompatibility class; NFκB: nuclear factor kappa-light- chain- enhancer of activated B cells; NK: natural killer cell; Th: helper T lymphocyte; TLR: Toll-like receptor; TNF: tumour necrosis factor\nNormal inflammation is self-limiting because the production of pro-inflammatory cytokines (Th1 cytokines) is followed almost immediately by the production of anti-inflammatory cytokines (Th2 cytokines; IL-1, IL-10, IL-13, etc.). Chronic inflammation seems to result when the initiating factors persist, or there is some sort of failure of the resolution process.\nDysfunction of the immune system and the loss of homeostatic equilibrium between TREG cells (IL- 10) and Th17 cells (IL-17) was observed in different pathological situations [16], and it is believed to increase the risk of viral infections, including SARS- coronavirus 2 (SARS-CoV-2) [14].\nSARS-CoV-2 is an enveloped positive-strand RNA virus in the family Coronaviridae, group 2b, which encodes the viral replicase and four structural proteins: spike (S), envelope (E) and membrane (M), present in the viral envelope, and nucleocapsid (N) [17].\nThe access route of SARS-CoV-2 is represented by a hydrophobic pocket of the extracellular catalytic domain of Angiotensin-converting enzyme 2 (ACE2) [18]. SARS-CoV peak S protein trimers bind ACE2, expressed in endothelial cells of the vasculature and in the epithelia of the lungs, intestine, heart, brain and kidney. SARS-CoV-2 enters the cell for endocytosis and membrane fusion. Once the virus has infected the cell, it follows a downregulation of ACE2 with a consequent local increase in the levels of Ang II, and the development of acute respiratory distress syndrome (ARDS) [19]. The role of ACE2 in the gut, for expression of neutral amino acid transporters, could explain diarrhoea and intestinal inflammation observed in COVID-19. Moreover, SARS-CoV2 protein E activates the NFκB inflammatory pathway with the consequent activation of MAPK p38, resulting in exacerbation of inflammation and immunopathology [20]. Following the SARS-CoV-2 infection, in the incubation stage and in the non-serious form of COVID-19, the immune system activates the specific adaptive immune response to eliminate the virus, which should be sufficient to block viral propagation and disease progression. The antiviral system functions well in the presence of general good health and an adequate genetic background. However, the presence of concomitant pathologies (obesity, cardiovascular diseases, diabetes, neurodegenerative diseases and cancer), malnutrition, and impaired immune response determine the spread of the virus and a massive destruction of the affected tissues, especially in organs that have high ACE2 expression [21]. As noted earlier, SARS-CoV-2 enters the cell via ACE2; that inactivates des-Arg bradykinin, which is a potent ligand of the bradykinin receptor type 1 (BDKRB1).This receptor, localized on endothelial cells, is up-regulated by inflammatory cytokines, which is unlike the B2 receptor, that is constituently expressed and is the receptor for bradykinin (BDK). BDK is produced from an inactive pre-protein kininogen through activation by the serine protease kallikrein; in addition, it is considered a potent regulator of blood pressure [22], because it induces vasodilation, natriuresis, and hypotension upon activation of the BDKRB2 receptor. BDK is strongly integrated with the RAS, and the BDK receptor signaling is increased by angiotensin’s action [23].\nInterestingly, ACE has a higher affinity for BDK [24] and therefore in conditions where ACE is low, the vasopressor system is moved toward a BDK-directed hypotensive axis. BDK takes part in the inflammatory response after injury and acts to induce pain via stimulation of the BDKRB1 receptor, which also causes neutrophil recruitment and a major vascular permeability [25, 26].\nDuring the infection, as long as the virus persists, there is dysfunction of ACE2 function, leading to the dysregulation of the kinin-kallikrein pathway and thus causing the angioedema [27]. Some evidence that the edema is bradykinin-generated includes resistance to corticosteroids, epinephrine, and antihistamines in the management of reducing the pulmonary edema in COVID-19 patients. In fact, the so called Bradykinin Storm is likely responsible for most of the observed COVID-19 symptoms.\nInflammation plays a fundamental role in the pathogenesis and progression of COVID-19, ranging from common colds to fatal cases of pneumonia due to the cytokine release syndrome (CRS) that affected patients, determining the severe conditions. In COVID-19 the homeostatic equilibrium between TREG cells (IL-10) and Th17 cells (IL-17) is broken: inflammatory cytokine levels (IL-1, TNF) are elevated in the lungs of COVID-19 patients, resulting in an increase in HA-synthase-2 (HAS2) in alveolar epithelial cells CD31+, EpCAM+ and fibroblasts. The imbalance between pro-inflammatory and anti-inflammatory cytokines, leads to the CRS, an excessive and damaging host inflammation [28]. As a consequence of CRS [29], due to a severe infection of SARS-CoV-2 of the respiratory epithelium, the ARDS was observed in COVID-19 [30]. Edema and an IL-1β mediated proinflammatory response were increased in the lung parenchyma. Macrophages and dendritic cells produce IL-1β through macro-molecular complexes called inflammasomes, including the major element present in the pulmonary tissue and the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome [20]. Following a precise stimulus, the activation and recruitment domain of caspase (ASC) and the catalytically inactive procaspase-1 assemble, the procaspase-1 turns into active caspase-1, the inactive pro-IL-1β matures in IL-1β and the NLRP3 inflammasome is activated. The NLRP3 inflammasomes and IL-1β driven proinflammatory cascades correlate with worsening of several respiratory diseases, including COVID-19.\nPatients affected by obesity showed a severe consequence of COVID-19 [31], due to the high concentrations of TNF-α, MCP-1 and IL-6 produced in the meantime by visceral and subcutaneous adipose tissue and by innate immunity [32]. Moreover, leptin, released by adipose tissue, helps to increase inflammatory milieu with a dysregulation of the immune response [33].\nThis umbrella review seeks to answer the question of whether a nutritional approach can be used to enhance the immune system’s response to obesity in obese patients affected by COVID-19.\nImmunonutrition has been based on the concept that malnutrition impairs immune function, used to modify inflammatory or immune responses. This concept may be applied to any situation in which a supply of specific nutrients is necessary to modify inflammatory or immune responses. Immunonutrients can promote patient recovery by inhibiting inflammatory responses and regulating immune function. Therefore, immunonutrition involves feeding enriched with various pharmaconutrients (arginine, glutamine, omega-3-fatty acids, ribonucleotides and certain trace elements and antioxidants compound, vitamins and minerals) to modulate inflammatory responses, the acquired immune response, and to improve patient outcomes [34].\nPersonalized immunonutrition for patients with obesity should be the first therapeutic choice to reduce the risk of infections and the disease course in COVID-19 patients. That therapeutic strategy could be effective in case of other potential epidemic infections. It would also allow a reduction of the enormous medical care cost supported by the National Health Service."}