LitCovid-sentences  

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Id Subject Object Predicate Lexical cue
T312 0-36 Sentence denotes Adaptive Immune Response in COVID-19
T313 38-73 Sentence denotes Functional Adaptive Immune Response
T314 74-178 Sentence denotes The functional but well-regulated adaptive immune response is necessary to overcome the viral infection.
T315 179-423 Sentence denotes Specifically, T cells when recruited to the site of infection engage in eliminating the infected cells and act in concordance with virus-specific neutralization antibodies to provide sustained immunity (Hor et al., 2015; De Biasi et al., 2020).
T316 424-750 Sentence denotes Considering the recent extensive work in understanding the functional early immune response during COVID-19, it appears that a complex interplay between T and B cell immune response along with patient-specific underlying health condition and genetic factors determines the recovery, as will be discussed in following sections.
T317 752-767 Sentence denotes T Cell Response
T318 768-981 Sentence denotes Generation of early adaptive immune response is critical for the selective elimination of virus-infected cells and neutralization of viral antigens, thereby preventing the damage to the underlying lung parenchyma.
T319 982-1187 Sentence denotes Cytokines, chemokines, PAMPs, and DAMPs released by infected ATII and activated AMs in the lung are adequate to mount a well-coordinated and regulated adaptive immune response by priming lung resident DCs.
T320 1188-1306 Sentence denotes After encountering the antigen-presenting DCs, naive CD4+ T cells differentiate into effector and memory CD4+ T cells.
T321 1307-1529 Sentence denotes At least five different CD4+ T cell lineages are known (TH1, TH2, TH17, TFH, and TREG cells) with prominent roles of TH1 and TFH cells in mounting antiviral response during SARS-CoV infection (Channappanavar et al., 2014).
T322 1530-1639 Sentence denotes Additionally, some studies have also shown a functional TH2 response in PBMCs derived from COVID-19 patients.
T323 1640-1773 Sentence denotes Release of TH2 specific cytokines like IL-4 and IL-5 was observed in vitro after these cells were stimulated (Weiskopf et al., 2020).
T324 1774-1921 Sentence denotes Similarly, these patients show enhanced production of IL-17 along with other TH17 cell-specific cytokines (Liu J. et al., 2020; Wu and Yang, 2020).
T325 1922-2128 Sentence denotes These findings suggest that the TH cell response in COVID-19 patients is complex concerning other infections, and this complexity may partly depend upon the prevailing pathophysiological state of a patient.
T326 2129-2293 Sentence denotes During viral infections like SARS-CoV, TH1 differentiation is influenced by IL-12 and IFN-γ secreted by DCs along with co-stimulatory signaling via B7-1/2 and CD28.
T327 2294-2431 Sentence denotes Whereas IL-6 secreted by DCs influence TFH differentiation to aid in antibody secretion by B cells (Tang et al., 2008; Lau et al., 2012).
T328 2432-2689 Sentence denotes Under the influence of chemokines (CCL3, CCL4, CCL5, CCL8), TH1 cells are recruited to the site of infection and are distinguished by the secretion of IL-2, IFN-γ, IL-12, and TNF-α as the main effector cytokines during SARS-CoV infections (Li et al., 2008).
T329 2690-2861 Sentence denotes Similarly, naive CD8+ T cells are activated by DCs by engaging MHC-I and TCR receptors, along with CD28-B7 co-stimulatory signaling and cytokines released by CD4+ T cells.
T330 2862-3010 Sentence denotes IL-2 secreted chiefly by CD4+ T cells is also implicated in their long-term maintenance and proliferation (Eickhoff et al., 2015; Hor et al., 2015).
T331 3011-3187 Sentence denotes Notably, CD8+ T cells could also be activated independently of help from CD4+ T cells under conditions where a robust IFN Type I response is present (Wiesel and Oxenius, 2012).
T332 3188-3404 Sentence denotes These activated CD8+ T cells [also referred to as cytotoxic T lymphocytes (CTLs)] get subsequently recruited to the effector organ under the influence of chemokines (CCL3, CCL4, CCL5, CXCL9, and CXCL10) (Nolz, 2015).
T333 3405-3604 Sentence denotes At the infected site, CTLs mount an antiviral response by directly killing the infected cells via secretion of cytotoxic molecules like granzymes, perforins, granulysin, and other cytotoxic granules.
T334 3605-3852 Sentence denotes Very recently, a study shows that CTLs secrete the granzymes and perforins as supramolecular attack particles (SMAPs) in a glycoprotein complex along with over 283 other proteins (including cytokines such as IFN-γ and TNF-α) (Bálint et al., 2020).
T335 3853-3954 Sentence denotes It will be interesting to know whether infection by CoVs also influences the release of SMAP by CTLs.
T336 3955-4096 Sentence denotes Animal studies have revealed the critical molecular insights of CD4+ cells in SARS-CoV clearance and attenuation of a pathological condition.
T337 4097-4236 Sentence denotes The depletion of CD4+ cells was associated with reduced virus clearance and interstitial pneumonitis (Jin et al., 2005; Wang et al., 2006).
T338 4237-4362 Sentence denotes In comparison, the adoptive transfer of virus-specific CD4+ and CD8+ T cells resulted in viral clearance (Zhao et al., 2010).
T339 4363-4579 Sentence denotes Similarly, clinical data has consistently shown the presence of antigen-specific CD4+ and CD8+ T cells in the recovered patients, akin to what was found in immunized animals, reviewed in Channappanavar et al. (2014).
T340 4580-4716 Sentence denotes On the other hand, severe cases of SARS-CoV infection were associated with a decline in T cells, as will be discussed in later sections.
T341 4717-4890 Sentence denotes Thus, based on these animal and clinical data, CD4+ T and CD8+ T cells were central to the antiviral response during SARS-CoV infection (Peng et al., 2006; Oh et al., 2012).
T342 4891-5006 Sentence denotes A subset of primed CD4+ and CD8+ T cells differentiates into long-acting memory cells after the infection subsides.
T343 5007-5180 Sentence denotes TCR-p: MHCII signaling helps in CD4+ T memory cell formation along with presence of cytokines like IL-2, IL-21 and interaction via CD40R-CD40L (Jaigirdar and MacLeod, 2015).
T344 5181-5328 Sentence denotes Similarly, This CD8+ T cell transition to memory cells take place under the influence of CD8+ TREG cells via secreted IL-10 (Laidlaw et al., 2015).
T345 5329-5466 Sentence denotes Long lasting CD4+ and CD8+ T memory cells were detected in the recovered SARS-CoV infected patients (Peng et al., 2006; Li et al., 2008).
T346 5467-5627 Sentence denotes Besides, other T cells subsets which are involved in antiviral response include unconventional NKT cells (CD56+) and MAIT (mucosa-associated invariant T) cells.
T347 5628-5797 Sentence denotes NKT cells act at the interface between innate and adaptive immune response and traffic to the site of infection under the influence of cytokines (Tsay and Zouali, 2018).
T348 5798-5906 Sentence denotes MAIT cells reside in the mucosal lining, such as in the lungs where they serve an immunoregulatory function.
T349 5907-6049 Sentence denotes Both these cell types play an essential role in the early clearance of the SARS-CoV-2, along with other T cell subsets (Grifoni et al., 2020).
T350 6050-6160 Sentence denotes Strategies to enhance their function are proposed to enhance the virial clearance during COVID-19 (Cao, 2020).
T351 6161-6331 Sentence denotes Role of these cells will be further discussed under the dysfunctional immune response in section “T and B Cell Response in Mild/Moderate and Recovered COVID-19 Patients.”
T352 6333-6348 Sentence denotes B Cell Response
T353 6349-6437 Sentence denotes B cells, along with T cells, form the central adaptive response during viral infections.
T354 6438-6568 Sentence denotes B cell response is highly specific, mounted by the virus-specific antibodies and other effector cytokines secreted by these cells.
T355 6569-6750 Sentence denotes B cell activation can be follicular helper T (TFH) cell-dependent, or in some instances, independent of helper cells; both instances are prevalent in COVID-19 (Mathew et al., 2020).
T356 6751-7034 Sentence denotes Under the influence of antigen-presenting dendritic cells, naïve CD4+ T cells differentiate into TFH cells, which are marked by high expressions of CXCR5 and IL-21, and low expressions of CCR7, IFN-γ, IL-4, and IL-17 (Rasheed et al., 2006; Nurieva et al., 2008; Morita et al., 2011).
T357 7035-7228 Sentence denotes The activated TFH cells interact with B cells via CD40R-CD40L and other associated receptors to induce the production of antigen-specific antibodies in a well-coordinated and regulated process.
T358 7229-7457 Sentence denotes This CD40R-CD40L interaction along with the secretion of IL-21 also allows the formation of long-lived memory B cells, while B cell-derived IL-6 and IL-27 help in reciprocal maintenance of TFH cells (Nurieva et al., 2008, 2009).
T359 7458-7622 Sentence denotes A previous animal study has shown the essential role of these helper cells in mounting an adequate antibody response against SARS-CoV infection (Chen et al., 2010).
T360 7623-7731 Sentence denotes The depletion of these cells was associated with a decline in antibody response and reduced viral clearance.
T361 7732-7850 Sentence denotes Thus, virus-specific antibodies produced by B cells are critical for an effective immune response mounted by the host.
T362 7851-8055 Sentence denotes These antibodies facilitate the clearance of the virus by either directly activating phagocytosis, opsonization, or activation of the antibody-dependent cellular cytotoxicity (ADCC) via effector NK cells.
T363 8056-8167 Sentence denotes Cytokines released by the activation of innate and adaptive immune systems also activate the complement system.
T364 8168-8317 Sentence denotes Viruses coated with the secreted antibodies from plasma cells eventually get eliminated by the complement system, reviewed by Risitano et al. (2020).
T365 8319-8389 Sentence denotes T and B Cell Response in Mild/Moderate and Recovered COVID-19 Patients
T366 8390-8535 Sentence denotes T cell response is an emerging critical determinant in keeping the SARS-CoV-2 infection under check (Huang C. et al., 2020; Liu J. et al., 2020).
T367 8536-8907 Sentence denotes Across studies, a decline in the number of these cells positively correlates with poor clinical outcome and immuno-pathogenesis, whereas adequate T cell number and proper effector function are prevalent in patients who develop mild disease symptoms or those who successfully recovered (Chen G. et al., 2020; Li H. et al., 2020; Sekine et al., 2020; Tan L. et al., 2020b).
T368 8908-9175 Sentence denotes Following a single patient (47-year-old woman) throughout the disease, Thevarajan et al. (2020) showed a concomitant increase in CD4+, CD8+, TFH cells, and antibody-secreting B cells from day seven after infection, which persisted for a week as the symptoms resolved.
T369 9176-9381 Sentence denotes Other studies revealed a similar trend of revival in T cell response in patients who have successfully cleared the virus (Anft et al., 2020; Braun et al., 2020; Chen X. et al., 2020; Chen N. et al., 2020).
T370 9382-9511 Sentence denotes SARS-CoV-2 specific reactive CD4+ and CD8+ T cells were found in 100 and 80% patients who needed mechanical ventilation (n = 10).
T371 9512-9600 Sentence denotes PBMCs derived from these patients showed reactivity against the S protein of SARS-CoV-2.
T372 9601-9796 Sentence denotes Further, in vitro stimulation of CD4+ T cells led to their differentiation into TH1, TH2, and TH17 subsets, as revealed by the expression of their corresponding cytokines (Weiskopf et al., 2020).
T373 9797-9881 Sentence denotes Interestingly, 20% of non-infected healthy controls also displayed reactive T cells.
T374 9882-10033 Sentence denotes The main limitation with this study was that the T response was studied only in critically ill patients and the small sample size was small to provide.
T375 10034-10211 Sentence denotes By studying a cohort of 18 COVID-19 patients and 64 healthy donors, Braun et al. (2020) found reactive CD4+ (83%) cells in blood-derived from the convalescing COVID-19 patients.
T376 10212-10281 Sentence denotes These reactive T cells were found specifically against the S protein.
T377 10282-10475 Sentence denotes Interestingly about 35% of SARS-CoV-2 seronegative healthy donors also showed the presence of S protein reactive CD4+ T cells indicating previous exposure to the related coronavirus infections.
T378 10476-10630 Sentence denotes Simultaneously, another study has found SARS-CoV-2 specific CD4+ T (100%) and CD8+ T (70%) cells in convalescent patients (n = 20) (Grifoni et al., 2020).
T379 10631-10836 Sentence denotes In addition to being majorly reactive against S protein, the study found additional targets of these T cells in the form of M, N, and ORF8 proteins and other non-structural proteins like NSP3, NSP4, ORF3a.
T380 10837-11064 Sentence denotes Further, in line with the study by Braun et al. (2020), T cells were found reactive against 40–60% of the SARS-CoV-2 uninfected patients, suggesting the presence of these reactive cells in response to previous viral infections.
T381 11065-11241 Sentence denotes In a yet to be a peer-reviewed article, Schulien et al. (2020) has extensively studied the SARS-CoV-2 epitope-specific role of CD8+ T cells in COVID-19 (Schulien et al., 2020).
T382 11242-11425 Sentence denotes The study found the presence of newly generated and pre-existing SARS-CoV-2 specific cells with the positive response seen in 88.4% of patients who had mild disease symptoms (n = 26).
T383 11426-11494 Sentence denotes The most substantial response was found against N protein and ORF3a.
T384 11495-11595 Sentence denotes Further, CD8+ T cells response was shown persistent even in the individuals who became seronegative.
T385 11596-11703 Sentence denotes In a patient studied longitudinally (70 days), CD8+ T cell response prolonged but antibody did not persist.
T386 11704-11956 Sentence denotes All these three studies taken together point toward the presence of functional and long-lasting reactive T cells in convalescent individuals, while others also suggest the presence of reactive T cells in critically ill patients (Weiskopf et al., 2020).
T387 11957-12133 Sentence denotes Thus, based on these studies, it appears that COVID-19 patients who exhibit mild disease symptoms and successfully recover, display functional and long-lasting T cell response.
T388 12134-12324 Sentence denotes However, these findings may not be definitive to provide a coherent functional view of these cells during recovery, as none of these studies compared the T cell response to disease severity.
T389 12325-12412 Sentence denotes A further difference in the time of sample collection may also complicate the findings.
T390 12413-12603 Sentence denotes In the study by Grifoni et al. (2020) samples were collected throughout 20–35 days after symptom onset, whereas Weiskopf et al. (2020), used samples collected after 14 days of ICU admission.
T391 12604-12694 Sentence denotes Thus, more studies under controlled clinical settings and large cohort size are warranted.
T392 12695-12858 Sentence denotes While addressing some of these concerns, a recent study explored T cell response in convalescent COVID-19 patients concerning disease severity (Peng et al., 2020).
T393 12859-13041 Sentence denotes The study found robust CD4+ and CD8+ memory T cell response in severe cases (n = 14) than mild (n = 28), suggesting long-lasting memory of these cells to keep the infection in check.
T394 13042-13093 Sentence denotes The limitation again here is the small sample size.
T395 13094-13240 Sentence denotes Therefore, more such studies with large sample size are needed to fully understand the impact of T cell response and its long-term sustainability.
T396 13241-13399 Sentence denotes B cell response has a temporal dynamic to human infecting CoVs, with a median time of detection for SARS-CoV as 14 days, reviewed by Huang A.T. et al. (2020).
T397 13400-13657 Sentence denotes The peak antibody titer for IgG and IgM, and detection time of neutralizing antibody varied across studies with a lower time point of seroconversion for IgG, IgM, and IgA as 15 days (Hsueh et al., 2004; Mo et al., 2006; Cao et al., 2007; Yang et al., 2009).
T398 13658-13745 Sentence denotes A more dynamic range of seroconversion was observed in sera from the COVID-19 patients.
T399 13746-13927 Sentence denotes A study by Liu X. et al. (2020) on 32 patients with varying disease severity has shown detectable IgM antibodies from day four and peaked at day 20, since the onset of the symptoms.
T400 13928-14004 Sentence denotes At the same time, IgG antibodies appeared after day 7 with a peak on day 25.
T401 14005-14125 Sentence denotes When compared to the disease severity, mild cases had peak IgM response earlier than in severe cases (day 17 vs day 21).
T402 14126-14258 Sentence denotes Further, severe cases exhibited more robust IgG antibody response than mild cases, as will be discussed in the subsequent section C.
T403 14259-14536 Sentence denotes In terms of the antibody response seen after symptom onset, a similar trend was shown by Liu X. et al. (2020) who detected IgM antibodies in SARS-CoV-2 infected patients between 3 and 6 days and IgG antibodies after day 8 of symptom onset, irrespective of the disease severity.
T404 14537-14670 Sentence denotes A study by Zhou P. et al. (2020) also found mean times of IgM, IgG, and neutralizing antibodies at 12, 14, and 11 days, respectively.
T405 14671-14808 Sentence denotes These reports were consistent with the reports from Wu et al. (2020) in which neutralizing antibodies were detected starting from day 10.
T406 14809-15009 Sentence denotes An elaborate antibody profile of 285 COVID-19 patients revealed 100% IgG and 94.1% IgM antibody response with a peak around the 3rd and 4th week after symptom onset, respectively (Long et al., 2020a).
T407 15010-15294 Sentence denotes Thus, for a successful viral clearance, an adequate adaptive immune response is generated around 2nd week after symptom onset and peaks around the 3rd week for IgM and at the beginning of 4th week for IgG (Ni et al., 2020; Thevarajan et al., 2020; Wu et al., 2020; Zhao et al., 2020).
T408 15295-15599 Sentence denotes Based on these and several other studies, it is evident that the antibody response is very dynamic in COVID-19 which may be dependent on the age, sex, genetic factors, underlying disease condition and most importantly, the type of assay used for serological testing (Guan et al., 2020; Hou et al., 2020).
T409 15600-15855 Sentence denotes Overall, these initial reports unequivocally suggest an integral role of the regulated adaptive immune response in the early clearance of virus and thereby attenuation of the disease condition in almost 80% of the patients who show mild/moderate symptoms.
T410 15856-16042 Sentence denotes On the other hand, in the rest, 20% severe and critically ill patients, disease symptoms positively correlate with the degree of lymphocytopenia, as will be discussed later in section C.
T411 16043-16144 Sentence denotes A schematic representation of the functional immune response during COVID-19 is depicted in Figure 3.
T412 16145-16223 Sentence denotes FIGURE 3 Clearance of virus infected cells by engaging adaptive immune cells.
T413 16224-16334 Sentence denotes Virus infected ATII cells activate the neighboring lung resident AMs by minimizing the CD200-200L interaction.
T414 16335-16444 Sentence denotes Additional requisite activation signals are provided by DAMPs, viral derived PAMPs, and cytokines like IFN-γ.
T415 16445-16738 Sentence denotes Activated AMs along with infected ATII derived molecules activate and recruit other innate immune cells, like circulating monocytes, dendritic cells, NK cells, and neutrophils which act in a coordinated manner to eventually recruit the adaptive effector immune cells like CTLs and CD4+T cells.
T416 16739-16875 Sentence denotes These adaptive immune cells then specifically eliminate virus infected cells while minimizing the damage to the nearby uninfected cells.
T417 16876-17059 Sentence denotes Thus, a well-coordinated and regulated adaptive immune response with help from innate immune cells is critical for initial antiviral response to limit the further spread of the virus.
T418 17060-17254 Sentence denotes Green arrows indicate the cytokines released by the respective activated immune cells which activate other immune cells as well as mount an antiviral response by acting on lung epithelial cells.
T419 17255-17434 Sentence denotes An immunological enigma still eluding researchers worldwide is how the majority of COVID-19 patients remain asymptomatic, and even some with high viral load (Lee S. et al., 2020).
T420 17435-17559 Sentence denotes This dilemma can be partly explained based on the effective functional early immune response generated by the T and B cells.
T421 17560-17702 Sentence denotes Mathew et al. (2020) used a multidimensional immunoprobing study and functionally characterized clinical features with immunological features.
T422 17703-17787 Sentence denotes This study defined three immunotypes based on 50 clinical and 200 immune parameters.
T423 17788-18021 Sentence denotes The immunotype 1 was positively associated with disease severity and had hyperactivated CD4+ and CD8+ T cells, with concomitant expression of exhaustion markers, indicating robust activation followed by the exhaustion of these cells.
T424 18022-18287 Sentence denotes This immunotype may thus be vulnerable to cytokine storm, as discussed later in section “Cytokine Storm in COVID-19 Patients.” Immunotype 2 was associated with the presence of proliferating memory B cells with the optimal activation status of CD4+ and CD8+ T cells.
T425 18288-18344 Sentence denotes This immunotype did not associate with disease severity.
T426 18345-18481 Sentence denotes The immunotype 3 had no activation status of CD4+ and CD8+ T cells, and thus exhibited an inverse correlation with the disease severity.
T427 18482-18665 Sentence denotes Overall, this study addressed some of the above questions that suggested that the presence of a regulated and functional adaptive immune response is key to preventing immunopathology.
T428 18666-18804 Sentence denotes In a similar study, the activation status of T cells associated with disease severity (acute, moderate, and severe) (Sekine et al., 2020).
T429 18805-18929 Sentence denotes The activation status of these T cells correlated with the presence of SARS-CoV-2 specific IgG antibodies in these patients.
T430 18930-19218 Sentence denotes Interestingly, T cells derived from convalescent mild and asymptomatic patients exhibited functional status when stimulated in vitro with SARS-CoV-2 specific antigens, suggesting the presence of well-regulated and functional T cell response in mild and asymptomatic convalescent patients.
T431 19219-19421 Sentence denotes Thus, in patients with high viral load, an immunopathological state can be prevented if the adequate and regulated adaptive immune response is present in association with the proper interferon response.
T432 19422-19709 Sentence denotes While in patients with compromised immune response, like in comorbid conditions, even a low viral load is sufficient to induce immunopathological changes, due to either ineffective immune response or uncontrolled hyper-activated response, as will be discussed in the subsequent sections.
T433 19711-19749 Sentence denotes Dysfunctional Adaptive Immune Response
T434 19750-19824 Sentence denotes A subset of COVID-19 patients displays robust activation of T and B cells.
T435 19825-19990 Sentence denotes These exaggerated T cell responses are specifically present in patients who manifest severe disease conditions and need mechanical ventilation (Herold et al., 2020).
T436 19991-20225 Sentence denotes Further, analysis of peripheral blood, BALF, and post-mortem lung samples of deceased patients reveal robust activation of T and B cells with a concomitant decline in the number of these cells (Kaneko et al., 2020; Liao et al., 2020).
T437 20226-20408 Sentence denotes Thus, it is becoming apparent that a subset of COVID-19 patients displays activated adaptive immune response, which augments hyper-inflammation, thereby leading to disease worsening.
T438 20409-20659 Sentence denotes In the subsequent section, we will specifically discuss the intricate role of T and B cells concerning their contribution to the development of the immunopathological state and how this critical antiviral immune response becomes awry during COVID-19.
T439 20661-20722 Sentence denotes Proinflammatory Cytokines Secreted by T Cells During COVID-19
T440 20723-20886 Sentence denotes Hyperinflammatory condition mediated by cytokines, chemokines and associated proinflammatory molecules which are secreted by both innate and adaptive immune cells.
T441 20887-21073 Sentence denotes However, during COVID-19, the relative contribution of adaptive immune cells towards proinflammatory molecules is still emerging, while the published studies suggest a complex interplay.
T442 21074-21279 Sentence denotes Profiling of 21 cytokines and chemokines in 39 patients and 24 healthy controls revealed increased levels of TH1 specific cytokines like IFN-γ, IL-2, and IL-12, and TH17 specific IL-17 in peripheral blood.
T443 21280-21410 Sentence denotes In comparison to the mild cases (n = 19), patients with severe disease (n = 10) condition had increased levels of these cytokines.
T444 21411-21530 Sentence denotes The limitation of this study was that the median age of severe cases was higher than in mild cases (Song et al., 2020).
T445 21531-21714 Sentence denotes Similarly, Zhou et al. (2020b) reported hyperactivated TH1 cell response with increased secretion of IFN-γ, GM-CSF, and IL-6 and with more robust expression in ICU cases than non-ICU.
T446 21715-22015 Sentence denotes Considering the age, gender and other associated factors, a large number of other studies have now confirmed that COVID-19 patients have increased levels of TH1 specific cytokines, with more robust levels seen in severe than mild cases (Huang C. et al., 2020; Xu Z. et al., 2020; Zhou et al., 2020b).
T447 22016-22157 Sentence denotes Similarly, CD8+ T cell-specific cytokines increased in COVID-19 patients, more pronounced in severe than mild condition (Zhou et al., 2020b).
T448 22158-22305 Sentence denotes Increased expression of GM-CSF was found in CD8+ T cells from ICU patients than non-ICU, while no difference was observed in IL-6 and TNF-α levels.
T449 22306-22603 Sentence denotes PBMCs derived from COVID-19 patients and stimulated in vitro showed an increase in expression of CCL2, CXCL10, Eotaxin, and IL-1RA, and stimulation of CD8+ T cells were associated with an increase in IFN-γ levels, which indicates the functional responsiveness of these cells (Mathew et al., 2020).
T450 22604-22705 Sentence denotes These studies thus suggest a robust activation of TH1 specific and CD8+ T cells in COVID-19 patients.
T451 22706-22818 Sentence denotes On the contrary, there are studies which show decreased cytokine expression by T cells in severe COVID-19 cases.
T452 22819-22949 Sentence denotes A study by Zheng H.Y. et al. (2020) showed a lower expression of IFN-γ, IL-2, and TNF-α in CD4+ T cells derived from severe cases.
T453 22950-23046 Sentence denotes Similarly, a decrease in IL-2+ CD8+ and IFN-γ+ CD8+ cells was also observed (Diao et al., 2020).
T454 23047-23338 Sentence denotes Although most studies point toward the robust activation and release of proinflammatory cytokines by CD4+ and CD8+ T cells, the discrepancy in latter studies could attribute to the functional exhaustion of these cells, which will we will discuss in section “Lymphocytopenia During COVID-19.”
T455 23339-23568 Sentence denotes Besides the presence of TH1 cytokines, TH2 cytokines like IL-4 and IL-5 and TH17 specific IL-17 were reported in some studies (Han et al., 2020; Huang C. et al., 2020; Song et al., 2020; Tan L. et al., 2020b; Xu Z. et al., 2020).
T456 23569-23743 Sentence denotes The presence of TH2 cytokines usually seen in mild cases may be accounted for by the presence of other respiratory conditions with TH2 specific response (Laing et al., 2020).
T457 23744-24074 Sentence denotes Overall, all these studies point toward the increased secretion of proinflammatory molecules by T lymphocytes in COVID-19, albeit with a heterogeneous response, which may be due to the variation in the age of the patients studied, different sampling times and presence of the comorbid condition, which needs further investigation.
T458 24076-24145 Sentence denotes Activation and Exhaustion Status of T Cells During COVID-19 Infection
T459 24146-24281 Sentence denotes The activation, exhaustion, and proliferation response of T and B cells are considered an integral determinant of the disease severity.
T460 24282-24553 Sentence denotes Unequivocally, studies have shown lymphocytopenia as a predictive marker which may also determine the disease severity in COVID-19 patients (Liu J. et al., 2020; Tan L. et al., 2020b; Wang et al., 2020b; Yang A.P. et al., 2020; Yang X. et al., 2020; Zhang et al., 2020a).
T461 24554-24669 Sentence denotes However, contradictory reports exist regarding the functional and exhaustion status of these cells during COVID-19.
T462 24670-24878 Sentence denotes Further, understanding these changes throughout the disease has remained a challenge, considering the complexity in the underlying immune response, comorbid condition, and previous exposure to the infections.
T463 24879-25038 Sentence denotes Peripheral blood study of a single patient (50-year male) revealed robust activation of CD4+ and CD8+ T cells marked by HLA-DR expression (Xu Z. et al., 2020).
T464 25039-25126 Sentence denotes However, the major limitation of this study was that only a single patient was studied.
T465 25127-25265 Sentence denotes Using multiparameter flow cytometry approach Kuri-Cervantes et al. (2020) studied 35 COVID-19 patients (n = 7 moderate and n = 28 severe).
T466 25266-25445 Sentence denotes The study revealed that a subset of severe cases displayed T cell activation as revealed by CD38 and HLA-DR expression in both CD4+ and CD8+ T cells (Kuri-Cervantes et al., 2020).
T467 25446-25640 Sentence denotes By analyzing, PBMCs derived from healthy (n = 5) and severe cases (n = 16), the authors found an increase in the percentage of cytotoxic CD8+ memory cells as revealed by perforin and granzyme B.
T468 25641-25756 Sentence denotes Similarly, a subset of severe cases had increased Ki-67 expressing CD4+ and CD8+ T cells, displaying proliferation.
T469 25757-25949 Sentence denotes At the same time, these findings revealed heterogeneous T cell response but overall suggested a skew towards the activation and proliferation status of these cells in a subset of severe cases.
T470 25950-26119 Sentence denotes The limitation of this finding is again the small sample size which may be the reason for the inconclusive findings of the T cell status concerning the disease severity.
T471 26120-26278 Sentence denotes Similar multiparameter flow cytometry approach was used by De Biasi et al. (2020) to study T cell response in healthy (n = 12) and COVID-19 patients (n = 21).
T472 26279-26389 Sentence denotes The study found activated status of CD4+ and CD8+ T cells as revealed by an increase in CD38+HLA-D population.
T473 26390-26532 Sentence denotes Activated status of the CD4+ T and CD8+ T cells was further confirmed by production of IFN-γ, TNF-α, IL-17, and IL-2 when stimulated in vitro.
T474 26533-26711 Sentence denotes The major limitation of this study was that the sample size was small, which restricted the comparison between the T cell responses across patients with various disease severity.
T475 26712-26854 Sentence denotes In another study, Song et al. (2020) showed the activated status of CD8+ T but not CD4+ T cells in severe (n = 9) than mild (n = 20) patients.
T476 26855-27011 Sentence denotes The activated status of CD8+ T cells reflected by the increased population of CD38+HLA-DR+, HLA-DR+, and CD38+HLA-DR+ marker expression (Song et al., 2020).
T477 27012-27177 Sentence denotes Further, CD8+ T cells were associated with increased cytolytic markers like granzyme B, perforin, and granulysin with more pronounced activation in severe than mild.
T478 27178-27305 Sentence denotes While across studies, it has become apparent that T cells show robust activation status in severe cases than mild and moderate.
T479 27306-27409 Sentence denotes These cells also exhibit exhaustion status, which may occur concomitantly with their activation status.
T480 27410-27633 Sentence denotes Deep immune profiling of 125 patients by Mathew et al. (2020) demonstrated that both CD4+ and CD8+ T cells exhibit activation status as revealed by coexpression of CD38 and HLA-DR which corresponded to the disease severity.
T481 27634-27759 Sentence denotes Further, these cells were also associated with concomitant expression of proliferation (Ki-67) and exhaustion (PD-1) markers.
T482 27760-27958 Sentence denotes This study thus suggests that hyperactivated status of T cells may eventually lead to their exhaustion, and thus these functional and exhaustion features of T cells may reflect the disease severity.
T483 27959-28113 Sentence denotes A study by Zheng M. et al. (2020) in a cohort of 68 COVID-19 patients revealed extensive CD8+ T cell exhaustion as shown by increased expression of NKG2A.
T484 28114-28341 Sentence denotes Intracellular cytokine staining (IFN-γ, IL-2, and granzyme B) further confirmed a decrease in the activation profile of these cells, which was more pronounced in severe (n = 55) than mild (n = 13) cases (Zheng M. et al., 2020).
T485 28342-28581 Sentence denotes As mentioned earlier in the study by Song et al. (2020) and De Biasi et al. (2020) T cells showed activation status that was also concomitantly seen with express of exhaustion markers PD-1 and TIM-3 on CD8+ T cells and TIM-3 on CD4+ cells.
T486 28582-28660 Sentence denotes The exhaustion was more pronounced in severe cases (n = 9) than mild (n = 20).
T487 28661-28766 Sentence denotes However, both these studies did not consider the age of the patients when comparing the disease severity.
T488 28767-28884 Sentence denotes Further, the study did not consider the temporal dynamics of these cells while measuring their functional properties.
T489 28885-29096 Sentence denotes In agreement, Zheng H.Y. et al. (2020) showed reduced functional activation of CD4+ T cells in severe (n = 6) than mild (n = 10) group as revealed by a lower proportion of IFN-γ and IL-2 expressing CD4+ T cells.
T490 29097-29196 Sentence denotes While IL-2 expressing CD4+ T cell population was also significantly lower in healthy vs mild group.
T491 29197-29377 Sentence denotes Further, CD8+ T cells displayed exhaustion as revealed by an increase in CTLA-4 in severe cases than mild and TGIT in severe than healthy, while PD-1 was more in mild than healthy.
T492 29378-29490 Sentence denotes Exhaustive states of both CD4+ and CD8+ T cells were also present in patients requiring ICU (Diao et al., 2020).
T493 29491-29622 Sentence denotes The exhaustive state was apparent by an increase in PD-1 and Tim-3 expression, which was more pronounced in CD8+ than CD4+ T cells.
T494 29623-29965 Sentence denotes These studies along with others thus suggest that robust activation followed by the exhaustion of CD4+ and CD8+ T cells may be responsible for the disease progression, while therapies like checkpoint inhibitors (anti-PD-1 antibody; NCT04268537) which may prevent T cell exhaustion and restore their functional state may benefit some patients.
T495 29966-30064 Sentence denotes More studies are necessary before using such an approach can be used for therapeutic intervention.
T496 30065-30184 Sentence denotes A post-mortem study of deceased COVID-19 patients conducted to find the status of these cells at the site of infection.
T497 30185-30354 Sentence denotes T cell profiling and their activation status in the lungs revealed an increase in the presence of CD4+ and CD8+ T cells exhibiting activation status (Song et al., 2020).
T498 30355-30468 Sentence denotes This increase in infiltration of these cells was concomitantly associated with their decline in peripheral blood.
T499 30469-30582 Sentence denotes Others presented a similar activation profile of CD8+ T cells (Kuri-Cervantes et al., 2020; Mathew et al., 2020).
T500 30583-30928 Sentence denotes This activated state of CD8+ T cells was consistently present across studies, with reports of immune profiling in BALF samples from COVID-19 patients, which showed increased CD4+ and CD8+ T cells in the lungs in both mild and severe cases along with the increased expression of CD8+ T cell cytolytic genes like GZMA and GZMK (Liao et al., 2020).
T501 30929-31127 Sentence denotes Thus, these studies point towards heterogeneous activation and exhaustion status of T cells in peripheral blood, while a more consistent activated status at the site of infection (lungs) (Figure 4).
T502 31128-31290 Sentence denotes FIGURE 4 T and B cell immune response during SARS-CoV-2 infection. (A) The activation status of CD4+ and CD8+ T in the circulation is indicated by CD38+ HLA-DR+.
T503 31291-31428 Sentence denotes These activated T cells are further recruited at the sites of infection (initially lungs) in the presence of their respective chemokines.
T504 31429-31646 Sentence denotes The activated CD4+ T cells are marked by the presence of cytokines like IFN-γ, IL-2, IL-12, IL-6, and GM-CSF, whereas activated CD8+T (cytotoxic T cells) are marked by the secretion of granzymes, perforins, and IFN-γ.
T505 31647-31975 Sentence denotes During SARS-CoV-2 infection, activated CD8+T cells exhibiting increased expression of granzyme A, B, and K (GZM-B, GZM-A, and GZM-K) were found in the lungs (Liao et al., 2020; Song et al., 2020; Zheng M. et al., 2020). (B) T cells were also found to exhibit exhausted state as marked by the expression of PD-1, Tim3, and NKG2A.
T506 31976-32242 Sentence denotes However, most studies showing exhausted T cells were confined to the peripheral blood, while lungs were mostly shown to have activated T cells but with concomitant expression of some exhaustive markers, suggesting that the activation state is followed by exhaustion.
T507 32243-32615 Sentence denotes The exhaustive T cells are marked by the reduced expression of respective chemokines and cytolytic granules. (C) Similarly, antibody-producing B cells (plasmablasts; PB) were shown to exhibit activation status as reflected by the expression of IL4R, TNFSF13B, and XBP1, while at the same time, the exhausted status of these cells was also reported in the peripheral blood.
T508 32616-32694 Sentence denotes Exhaustive state of B cells is reflected by a decrease in antibody production.
T509 32695-32884 Sentence denotes Further, it appears that unlike CD4+ T cells, the activation status of CD8+ T cells is more pronounced, which may account for their relatively faster exhaustion state (Wherry et al., 2007).
T510 32885-33093 Sentence denotes Interestingly, by studying the CD8+T cell response in convalescent patients, Habel et al. (2020) found that these cells skewed toward naïve, stem cell and central memory phenotypes, with low effector T cells.
T511 33094-33210 Sentence denotes While comparing the response with Influenza A viruses, SARS-CoV-2 directed CD8+ T exhibit relatively lower response.
T512 33211-33553 Sentence denotes Others have also shown a significant decline in CD8+ T cell subsets (naïve, effector, and memory) in COVID-19 patients, with a more pronounced decline in critical (n = 3) than severe (n = 5), and mild (n = 4), suggesting their robust activation during early disease followed by exhaustion during the critical condition (Wang W. et al., 2020).
T513 33554-33674 Sentence denotes On the contrary, CD4+ T cells were higher in the mild and critical cases than severe cases and healthy control (n = 12).
T514 33675-33904 Sentence denotes These results imply that the overall T cell response is heterogenous, while CD8+ response, though robust during infection and correlates with the disease severity; but the response may not be long-lasting, at least in some cases.
T515 33905-33986 Sentence denotes Both CD4+ and CD8+ T cells also exhibit dysregulated response (Qin et al., 2020).
T516 33987-34105 Sentence denotes Decreased levels of CD4+ regulatory cells as marked by CD3+ CD4+ CD25+ CD127low+ population was found in severe cases.
T517 34106-34203 Sentence denotes Similarly, the study found decreased CD8+ suppressor T cells (CD3+, CD8+, CD28+) in severe cases.
T518 34204-34432 Sentence denotes Overall, more comprehensive studies are warranted with larger cohort size, to profile local vs systemic T cell response and persistence simultaneously, and correlate these responses with disease severity in age-matched patients.
T519 34434-34474 Sentence denotes Impaired B Cell Response During COVID-19
T520 34475-34599 Sentence denotes Regulated and controlled B cell response is critical for the effective immune response against the CoVs, as discussed above.
T521 34600-34717 Sentence denotes However, under certain conditions, B cell response may be detrimental and aggravate the underlying disease condition.
T522 34718-34905 Sentence denotes A notion has emerged, which suggests that in COVID-19 patients, B cell number though reduced, but these cells display robust activation in some cases that correlate with disease severity.
T523 34906-35091 Sentence denotes Deep immune profiling integrated with computational approach revealed intricate relations of B cell response with clinical parameters at various stages of the COVID-19 disease severity.
T524 35092-35204 Sentence denotes These cells express proliferation (Ki67+), differentiation (CD27+ CD38+), as well as exhaustion markers (PD-1+).
T525 35205-35372 Sentence denotes More robust expression of these markers was observed in severe cases compared to mild-moderate, with an overall decrease in memory B cell number (Mathew et al., 2020).
T526 35373-35527 Sentence denotes Further, 70% of the patients reported have IgG and IgM S protein-specific antibodies, suggesting activation status of the antibody-secreting plasmablasts.
T527 35528-35699 Sentence denotes Thus, this study shows that B cells, in severe cases, display concomitant activation and exhaustion markers, while mild cases or healthy controls showed a normal response.
T528 35700-35796 Sentence denotes However, how this activated status of B cells had an impact on disease severity was not studied.
T529 35797-36017 Sentence denotes By looking at the alleged relationship of activated B cells with disease severity, Woodruff et al. (2020) showed robust activation status of extrafollicular B cells which resembled their behavior in autoimmune condition.
T530 36018-36259 Sentence denotes The activation status of these cells was found more pronounced in critically ill patients (n = 10) than non-critical (n = 7) and healthy control (n = 17), which correlated with SARS-CoV-2-specific antibody production and disease progression.
T531 36260-36478 Sentence denotes Further, an increase in antibody-secreting cells (ASCs) was found in critically ill cases compared to non-severe cases along with an increase in S protein-specific antibodies, probably with a non-neutralizing property.
T532 36479-36689 Sentence denotes This study shows that in some patients with a critical disease condition, robust B cell response and presence of SARS-CoV-2 antigen-specific antibodies may be associated with worsening of the disease condition.
T533 36690-36777 Sentence denotes The ASCs were identified as the population of cells with CD138+ and CD21low expression.
T534 36778-36866 Sentence denotes However, no comparison was drawn between various age groups concerning disease severity.
T535 36867-37003 Sentence denotes While across studies, B cell activation is apparent in severe cases, it is subsequently associated with a sharp decline in their number.
T536 37004-37144 Sentence denotes Various mechanisms may be responsible for this decline, among which B cell exhaustion is one, but still poorly understood (Yi et al., 2010).
T537 37145-37252 Sentence denotes A recent study has provided mechanistic insights into how some cases of COVID-19 exhibit low B cell number.
T538 37253-37481 Sentence denotes Kaneko et al. (2020) studied the post-mortem samples (n = 11) of thoracic lymph nodes and spleens and found that Bcl-6+ germinal center (GC) B cells highly reduced in these patients in comparison to non-COVID-19 control (n = 6).
T539 37482-37630 Sentence denotes This decline in GC was also associated with a decrease in TFH cell differentiation and an increase in the number of TH1 cells (Kaneko et al., 2020).
T540 37631-37709 Sentence denotes Further, an increase in expression of TNF-α levels was found in the follicles.
T541 37710-37942 Sentence denotes Based on previous studies that TNF-α inhibits the lymphoid follicular development, and high levels of this pleiotropic cytokine is the hallmark of COVID-19, the authors attributed the reduction in GC to high levels of this cytokine.
T542 37943-38116 Sentence denotes In addition to the study in post-mortem samples, the authors conducted B cell analysis in peripheral blood samples from COVID-19 patients at different stages of the disease.
T543 38117-38413 Sentence denotes In line with the post-mortem data, patients with severe disease condition (n = 25) had a significant decrease in the number of naïve B cells, CD19+ B cells, and follicular B cell subsets in comparison to the healthy controls (n = 4), convalescent patients (n = 39), and moderate patients (n = 4).
T544 38414-38508 Sentence denotes Thus, this study provides a probable cause for the B cell decline in severe cases of Covid-19.
T545 38509-38680 Sentence denotes However, there was a significant difference in the mean age of severe patients (higher between 58 and 60) than the control, convalescent, and moderate group (30–45 years).
T546 38681-38766 Sentence denotes Thus, the effect of age on the decline in B cells cannot be undermined in this study.
T547 38767-38966 Sentence denotes More studies are needed to specifically look into the B cell number and activation status in COVID-19 patients concerning the disease severity to get a clear understanding of the role of these cells.
T548 38968-38997 Sentence denotes Antibody Dynamics in COVID-19
T549 38998-39136 Sentence denotes Antibody-based therapy is being considered as a potential intervention for COVID-19, owing to the successful preliminary results with CPT.
T550 39137-39315 Sentence denotes However, this treatment approach may be associated with the risk of exacerbating COVID-19 severity, based on the experience from previous viral infections (Salazar et al., 2017).
T551 39316-39534 Sentence denotes Further, like previous SARS-CoV infections, antibody response may not always favor viral clearance, instead of contributing to the underlying immunopathology in some instances (Zhang et al., 2006; Newton et al., 2016).
T552 39535-39764 Sentence denotes This immunopathological state may thus attribute to factors such as robust and unregulated activation of B cells, ADE, presence of cross-reactive but non-neutralizing antibodies, and failure to mount a controlled B cell response.
T553 39765-39961 Sentence denotes Across studies, higher antibody titers detected in patients with severe and critical condition in comparison to non-severe cases (Long et al., 2020a; Gudbjartsson et al., 2020; Zhao et al., 2020).
T554 39962-40227 Sentence denotes One can argue that higher antibody titer should be beneficial to provide an adequate antiviral response but can be countered by the finding that higher antibody titers found in a large number of severe cases and patients requiring ventilation (Kaneko et al., 2020).
T555 40228-40391 Sentence denotes This contradiction is yet to resolve, and the emerging data suggest that higher antibody response may reflect the over-activation and uncontrolled B cell response.
T556 40392-40516 Sentence denotes Zheng M. et al. (2020) showed the presence of RBD-specific IgG and IgA antibodies in patients with severe disease condition.
T557 40517-40592 Sentence denotes The study included 13 severe and 41 non-severe cases of various age groups.
T558 40593-40752 Sentence denotes Along with increased IgG and IgA levels, severe cases also had an increased number of antibody-secreting cells and TFH cells, which aid in antibody production.
T559 40753-40921 Sentence denotes Further, a close correlation of proinflammatory cytokines and chemokines like IL-6, CXCL10 and complement activation marker C5a found with the severe disease condition.
T560 40922-41049 Sentence denotes This study provided a direct relation of inflammatory response with humoral immune response in context to the disease severity.
T561 41050-41152 Sentence denotes However, the antigen-neutralizing property of these SARS-CoV-2 specific antibodies was not determined.
T562 41153-41336 Sentence denotes Further, a low sample size of severe cases was another limiting factor to provide a definitive conclusion that robust antibody response may positively correlate with disease severity.
T563 41337-41469 Sentence denotes Similarly, Zhao et al. (2020) studied antibody response in 173 clinically diagnosed COVID-19 patients with a median age of 48 years.
T564 41470-41622 Sentence denotes Among these, nine patients (three critical and six non-critical) studied longitudinally for the relation of antibody response with the disease severity.
T565 41623-41702 Sentence denotes Antibody titer was higher in the critical patients as compared to non-critical.
T566 41703-41916 Sentence denotes This higher titer of antibodies was not reflected by the clearance of the virus, thus suggesting that antibody response in critical cases may be associated with worse disease outcome rather than protective effect.
T567 41917-42014 Sentence denotes However, like other studies, this study also suffers from the same limitation of low sample size.
T568 42015-42229 Sentence denotes In line with the notion that antibody response is higher in severe patients, a large population study (n = 30,576 persons from Iceland) (Gudbjartsson et al., 2020) conducted in Iceland revealed similar observation.
T569 42230-42418 Sentence denotes The study provided a comprehensive account of the relation of antibody response concerning age, sex, body-mass index, drugs habits like smoking and the use of anti-inflammatory medication.
T570 42419-42587 Sentence denotes Results show that patients with smoking habit and who were on anti-inflammatory medication, had lower antibody levels, while body mass index had a positive association.
T571 42588-42777 Sentence denotes The data thus suggest that antibody response may not always favor clearance of the virus, but in some instances, higher antibody levels may make the patients more vulnerable to the disease.
T572 42778-42926 Sentence denotes This detrimental relation of antibody response with poor disease outcome was also prevalent in the previous SARS-CoV infection (Zhang et al., 2006).
T573 42927-43172 Sentence denotes In a study on the sera samples obtained from SARS-CoV infected patients, a faster S protein-specific antibody response was found in patients who did not survive (14.7 days), as compared with the patients who recovered from the disease (20 days).
T574 43173-43305 Sentence denotes Further, the antibody titer was significantly higher in the deceased patients with faster production than in the recovered patients.
T575 43306-43497 Sentence denotes To mechanistically understand why antibody response has a more detrimental effect than protective, Liu et al. (2019) studied viral antibody response in animal models (Chinese rhesus monkeys).
T576 43498-43667 Sentence denotes When animals infected with the SARS-CoV and adoptively transferred with anti-S protein IgG could not prevent the infection but instead displayed severe disease symptoms.
T577 43668-43865 Sentence denotes Presence of the S protein antibody abrogated wound healing, induced macrophage/monocyte infiltration into the lungs and caused the release of proinflammatory cytokine followed by acute lung injury.
T578 43866-44032 Sentence denotes This study thus demonstrated that the presence of S protein-specific antibody might have a deleterious effect in inducing lung injury, irrespective of the viral load.
T579 44033-44164 Sentence denotes However, since mechanistic details are difficult to discern in clinical samples, more studies in animal models need to be explored.
T580 44165-44454 Sentence denotes Further, owing to the dynamics of antibody response in clinical samples concerning underlying disease condition, age, and genetic factors; animal models will provide a cleaner system to delineate the antibody dynamics with respect to disease severity (Guan et al., 2020; Hou et al., 2020).
T581 44455-44584 Sentence denotes Contrary to B cell activation, some studies have shown lower antibody durability in both mild and severe cases (Yu et al., 2020).
T582 44585-44739 Sentence denotes In a longitudinal study on a 26-year-old woman with a moderate disease condition, antibody response disappeared within three months (Liu A. et al., 2020).
T583 44740-44941 Sentence denotes In a sizable cohort of samples, asymptomatic patients (n = 37 with median age 41 years) had relatively lower durability of the IgG and IgM antibodies in comparison to the symptomatic patients (n = 37).
T584 44942-45055 Sentence denotes Further, the viral shedding in the asymptomatic group was higher than the symptomatic group (Long et al., 2020b).
T585 45056-45258 Sentence denotes Similarly, Ibarrondo et al. has shown the same antibody durability in 34 COVID-19 patients with a mean age of 43 years when studied longitudinally for a period of upto 4 months (Ibarrondo et al., 2020).
T586 45259-45380 Sentence denotes The authors found a significant decline in IgG antibodies in the sera of convalescent patients with mostly mild symptoms.
T587 45381-45546 Sentence denotes A declining trend was seen for multiple SARS-CoV-2 antibodies like IgG N, IgM, IgG S1, and IgA S1 in the longitudinal analysis (n = 487) (Gudbjartsson et al., 2020).
T588 45547-45698 Sentence denotes In another longitudinal study, the disappearance of S and N protein-specific antibodies was observed within 3 months of recovery (Liu A. et al., 2020).
T589 45699-46027 Sentence denotes Based on these reports, we can infer that the antibody response in some COVID-19 patients may not be long-lasting, which poses a challenge for antibody-based therapy and vaccine research—further, these data caution towards chances of reinfection, as shown to be the case with other seasonal coronaviruses (Edridge et al., 2020).
T590 46028-46166 Sentence denotes However, larger cohort size and longer time frame longitudinal studies are needed to find the durability of antibody response in COVID-19.
T591 46167-46318 Sentence denotes Further, a comparison of various disease states with corresponding antibody response will provide clearer insight as to how this response is regulated.
T592 46319-46553 Sentence denotes It appears that in patients with severe disease symptoms, TNF-α may influence the GC and hence B cell number (Kaneko et al., 2020), whether the same holds for asymptomatic patients with compromised antibody durability remains elusive.
T593 46554-46687 Sentence denotes This dynamic antibody response is critical while considering convalescent plasma therapy (CPT) for severe or critically ill patients.
T594 46688-46820 Sentence denotes If a patient already has sufficient antibodies, CPT may not be a viable treatment option (Anderson et al., 2020; Duan et al., 2020).
T595 46821-46964 Sentence denotes While many studies have reported success with CPT, some studies have shown no added beneficial effects with this approach (Li L. et al., 2020).
T596 46965-47280 Sentence denotes Thus, pre-caution should be taken while using this approach, i.e., if a patient already has adequate virus-specific antibodies or presence of cross-reactive and auto-antibodies, plasma therapy may do more harm than good, which may be the reason with non-responsiveness of CPT in some patients (Nagoba et al., 2020).
T597 47282-47346 Sentence denotes SARS-CoV-2 Antibody Cross-Reactivity and Neutralization Property
T598 47347-47431 Sentence denotes A range of SARS-CoV specific antibodies have shown cross-reactivity with SARS-CoV-2.
T599 47432-47516 Sentence denotes These antibodies target S protein and mostly the RBD region (Hoffmann et al., 2020).
T600 47517-47665 Sentence denotes Monoclonal antibodies against SARS-CoV such as CR3022 and S309 have shown cross-reactivity with SARS-CoV-2 (Pinto et al., 2020; Wang et al., 2020a).
T601 47666-47922 Sentence denotes Similarly, in a study of 285 patients, S protein-specific antibodies from SARS-CoV showed cross-reactivity with CoV-2 N protein in a subset of patients (n = 5), whereas no-cross reactivity was detected against S1 subunit of SARS-CoV-2 (Long et al., 2020a).
T602 47923-48040 Sentence denotes Thus, the cross-reactive nature of some of these antibodies may ensure their efficacy against multiple coronaviruses.
T603 48041-48183 Sentence denotes However, at the same time, these cross-reactive antibodies should also have neutralizing property; otherwise, they will have a harmful effect.
T604 48184-48308 Sentence denotes A recent study explored the cross-reactive and neutralization property of these antibodies simultaneously (Lv et al., 2020).
T605 48309-48515 Sentence denotes This study used plasma from 15 SARS-CoV-2 and 7 SARS-CoV patients and found a high degree of cross-reactivity between the antibody response from these samples, but a very low antibody neutralizing property.
T606 48516-48597 Sentence denotes These results were further confirmed in animal models of SARS-CoV-2 and SARS-CoV.
T607 48598-48776 Sentence denotes While S309 antibody showed better neutralization property against SARS-CoV-2, the neutralization properties for CR3022 are not yet known (Pinto et al., 2020; Wang et al., 2020a).
T608 48777-48975 Sentence denotes Thus, although a high degree of cross-reactivity of the antibody response from SARS-CoV-2 can be found with other related CoVs, the neutralizing property of these antibodies may be epitope specific.
T609 48976-49202 Sentence denotes The weak neutralizing property of such cross-reactive antibodies should thoroughly be tested before usage as a therapeutic intervention, to prevent the complications which may arise due to antibody-dependent enhancement (ADE).
T610 49203-49285 Sentence denotes These factors also become essential while considering convalescent plasma therapy.
T611 49286-49403 Sentence denotes In an elegant recent study, Cao et al. (2020) performed sc-RNA-seq of B cells from 60 convalescent COVID-19 patients.
T612 49404-49528 Sentence denotes The study led to the identification of 14 neutralizing antibodies, among which one (BD-368-2) showed the most potent effect.
T613 49529-49659 Sentence denotes BD-368-2 was further explored for its efficacy in animal models and showed therapeutic potential in SARS-CoV-2 transgenic animals.
T614 49660-49900 Sentence denotes Further, the study suggested the use of two different monoclonal antibodies targeting different epitopes as a more viable therapeutic intervention than a single antibody, which is impressive considering the emerging mutations in SARS-CoV-2.
T615 49901-50057 Sentence denotes Thus, more research in this direction is needed to find antibodies with potent neutralization property for targeted therapy to alleviate the disease burden.
T616 50059-50101 Sentence denotes Antibody Dependent Enhancement in COVID-19
T617 50102-50212 Sentence denotes Non-neutralizing but cross-reactive antibodies may lead to ADE and hence enhance the immunopathological state.
T618 50213-50458 Sentence denotes ADE can occur through various pathways, the most important among which include endocytosis of antibody conjugated virus by the phagocytic cells (via Fc gamma receptor IIa (FcγRIIa) and enhanced antibody immune complex formation (Kulkarni, 2020).
T619 50459-50664 Sentence denotes Virus uptake by the phagocytic cells induces robust propagation and hence may further aggravate the disease condition, while antibody immune complex formation may generate a high pro-inflammatory response.
T620 50665-50862 Sentence denotes Experience from previous viral infections has shown that ADE may lead to worse disease outcome in some patients with the presence of non-neutralizing antibodies, reviewed by Lee W.S. et al. (2020).
T621 50863-50958 Sentence denotes In vitro studies on monocytes and macrophages have shown ADE in SARS-CoV (Flipse et al., 2016).
T622 50959-51086 Sentence denotes However, no definitive clinical data is available that indicates the occurrence of ADE during SARS-CoV or SARS-CoV-2 infection.
T623 51087-51309 Sentence denotes Nevertheless, based on the substantial cross-reactivity between various epitope regions of CoVs, some patients may exhibit ADE due to the presence of cross-reactive but non-neutralizing antibodies from previous infections.
T624 51311-51345 Sentence denotes Unconventional T Cells in COVID-19
T625 51346-51500 Sentence denotes Bronchial alveolar lavage fluid analysis of 3 COVID-19 patients reveals a high number of NKT cells during the acute phase of infection (Kim et al., 2020).
T626 51501-51576 Sentence denotes This increase in NKT cells was similarly reflected in the peripheral blood.
T627 51577-51664 Sentence denotes Conversely, a decline in the number of these cells was found during the recovery phase.
T628 51665-51862 Sentence denotes These results thus suggest a close correlation of the NKT cell activity in COVID-19 and the presence of these cells may be required for the clearance of virus during the initial phase of infection.
T629 51863-52025 Sentence denotes Concomitantly, increased infiltration and activity of these cells may lead to a more severe outcome associated with eosinophilic pneumonia, as shown in one study.
T630 52026-52154 Sentence denotes However, no direct correlation of these cells types with disease severity was found, probably due to meagre sample size (n = 3).
T631 52155-52325 Sentence denotes Further, the samples used in this study were collected at different time points after the onset of symptoms, which may have complicated the interpretation of the results.
T632 52326-52629 Sentence denotes In another study on 30 COVID-19 patients with a varied range of disease severity from mild, moderate to severe, a reduction in the total peripheral blood NKT cells was seen across groups, with no difference in the overall number between ICU (n = 10) and non-ICU patients (n = 11) (Mazzoni et al., 2020).
T633 52630-52836 Sentence denotes Similarly, a study by Jouan et al. (2020) found a decrease in NKT and MAIT cells in the peripheral blood of COVID-19 patients (n = 30, with varied disease severity) as compared to healthy controls (n = 20).
T634 52837-53112 Sentence denotes This decline in circulating MAIT cells was concomitantly associated with an increase in these cells in the endotracheal aspirates (ETA) obtained from critically ill patients who needed mechanical ventilation (n = 12), while no changes in NKT cell number in ETA were detected.
T635 53113-53272 Sentence denotes The presence of circulating IL-18 reflected the activation of these cells, and the expression of PD-1 suggested subsequent exhaustion throughout the infection.
T636 53273-53430 Sentence denotes This study thus indicates that the presence of the activated status of these unconventional T cells may serve as a predictive assessment of disease severity.
T637 53431-53666 Sentence denotes More research about the activation, proliferation and differentiation status of these cells to the disease severity and local vs systemic effect is needed to fully understand their contribution in COVID-19 (Chen and John Wherry, 2020).
T638 53668-53699 Sentence denotes Lymphocytopenia During COVID-19
T639 53700-53976 Sentence denotes A drastic decrease in the number of circulating lymphocytes (lymphocytopenia) in severe and critically ill COVID-19 patients is now well appreciated (Huang C. et al., 2020; Liao et al., 2020; Liu et al., 2020a; Mathew et al., 2020; Zhou F. et al., 2020; Zhou P. et al., 2020).
T640 53977-54103 Sentence denotes Interestingly, restoration in the lymphocyte count is also consistently seen during the recovery phase (Chen Y. et al., 2020).
T641 54104-54240 Sentence denotes Based on these early findings, lymphocytopenia is considered a predictive indicator of COVID-19 disease severity (Tan L. et al., 2020b).
T642 54241-54459 Sentence denotes Although the molecular mechanisms associated with lymphocytopenia during SARS-CoV-2 are not known, emerging evidence suggests the role of multiple factors based on the correlations drawn from previous viral infections.
T643 54460-54788 Sentence denotes The decline in lymphocyte numbers in circulation can be attributed to altered chemokine and cytokine signaling responsible for the recruitment and activation/inhibition of these cells, increased infiltration to the site of infection, and cell death by apoptosis and/or necrosis (Wherry and Kurachi, 2015; Walling and Kim, 2018).
T644 54789-54975 Sentence denotes Immune profiles of COVID-19 patients show adequate levels of chemokines and cytokines involved in the maintenance of T and B cell phenotypes (Yang X. et al., 2020; Yang Y. et al., 2020).
T645 54976-55088 Sentence denotes Chemokines and cytokines responsible for CD8+ T cells priming and chemotaxis were also detected in the patients.
T646 55089-55319 Sentence denotes Similarly, cytokines responsible for B cell activation and proliferation signals were sufficiently present, thus excluding the possibility that lymphocytopenia may be a result of impaired activation signals or chemokine signaling.
T647 55320-55547 Sentence denotes Interestingly, a recent study suggests that severely ill COVID-19 patients had lower levels of activated (CD11a+) and terminally differentiated (CD57+) peripheral blood CD4+ and CD8+ T cells (which are also S-protein reactive).
T648 55548-55686 Sentence denotes The decline in the number of these cells can attribute to their concomitant migration to the infected regions under inflammatory response.
T649 55687-55881 Sentence denotes Similarly, another study has shown lymphocytopenia in peripheral blood along with a concomitant increase in the activation profile and the number of these cells in the lungs (Song et al., 2020).
T650 55882-56038 Sentence denotes Homing of these activated T cells to the site of infection may thus be associated with the worsening of the disease by amplifying the proinflammatory state.
T651 56039-56141 Sentence denotes A single patient analysis revealed increased CD4+ and CD8+ T cells in the BALF (Voiriot et al., 2020).
T652 56142-56353 Sentence denotes ScRNA-seq in BALF followed by cluster analysis revealed the presence of CD8+ T cells with proliferative phenotype in severe cases, whereas moderate cases exhibited clonal expansion phenotype (Liao et al., 2020).
T653 56354-56630 Sentence denotes From these accounts, it is indicative that increased migration of activated T cells to the site of infection may be one of the reasons for lymphocytopenia (in the blood) and the remaining T cells in the blood may eventually become dysfunctional (exhausted) as discussed below.
T654 56631-56785 Sentence denotes The decline in circulating lymphocyte number in COVID-19 patients can also attribute to the ‘exhausted’ state of these cells (Chen and John Wherry, 2020).
T655 56786-56955 Sentence denotes The heightened viral load and presence of specific inhibitory signals bring about changes in the transcriptional and effector profile of T cells in a coordinated manner.
T656 56956-57151 Sentence denotes Initially, they lose their property to secrete effector cytokines and gradually proceed to reduced expression of essential maintenance and activation surface receptors (Wherry and Kurachi, 2015).
T657 57152-57342 Sentence denotes A subsequent increase in the expression of inhibitory receptors and associated morphological changes result in the elimination of these cells from the circulation (Wherry and Kurachi, 2015).
T658 57343-57618 Sentence denotes CD4+ T cell exhaustion determines their insufficient secretion of effector molecules like IL-2, IL-10, IL-21, IFN-γ and TNF-α with a concomitant increase in inhibitory molecular signaling by PD-1, CTLA-4, LAG-3, CD244 (2B4), and TIM-3 (Blank et al., 2019; Dong et al., 2019).
T659 57619-57735 Sentence denotes Similarly, CD8+ T cell exhaustion is determined by reduced expression of IL-2, IFN-γ, TNF-α, and cytolytic granules.
T660 57736-57997 Sentence denotes Besides, decreased expression of T cell maintenance receptors CD122 and CD127, and increase in inhibitory receptor signaling via PD-1, CTLA-4, NKG2A, TIGIT, LAG-3, CD244 (2B4), and CD160 also mark their exhaustion (Wherry and Kurachi, 2015; Blank et al., 2019).
T661 57998-58222 Sentence denotes B cell exhaustion is also demonstrated similar to T cell exhaustion with an expression of inhibitory receptors PD-1, CD22, and LAIR-1 but the exhaustion profile of these cells is relatively unexplored (Moir and Fauci, 2014).
T662 58223-58351 Sentence denotes A large body of evidence suggests functional exhaustion of CD8+ T and CD4+ T cells in the peripheral blood of COVID-19 patients.
T663 58352-58549 Sentence denotes In some instances, exhaustion markers are concomitantly expressed along with activation and proliferation markers, as discussed above (Diao et al., 2020; Mathew et al., 2020; Mazzoni et al., 2020).
T664 58550-58697 Sentence denotes Moreover, increased expression of exhaustion-related genes like BATF, IRF4, and CD274 also correlated with disease severity (Hadjadj et al., 2020).
T665 58698-58815 Sentence denotes Interestingly, increased apoptosis of T cells became evident in severe cases as compared to mild/moderate conditions.
T666 58816-58960 Sentence denotes Thus, one way to explain lymphocytopenia in COVID-19 patients is that after the onset of symptoms, T cells are primed to overcome the infection.
T667 58961-59169 Sentence denotes However, in cases where viral infection persists, these cells attain robust activation, which may do more harm than good, as seen in severe and critically ill patients reviewed by Chen and John Wherry (2020).
T668 59170-59384 Sentence denotes Thus, the exhaustion of these cells precedes robust activation response, and eventually, they get eliminated from the circulation, as has been seen with previous viral infections (Wherry, 2011; Blank et al., 2019).
T669 59385-59563 Sentence denotes For example, during acute infection by lymphocytic choriomeningitis virus (LCMV), CD8+ T cells were shown to exhibit functional activation status and develop into memory T cells.
T670 59564-59746 Sentence denotes In contrast, during chronic infection, CD8+ T cells had impaired effector function and displayed profound exhaustion followed by apoptosis (Barber et al., 2006; Wherry et al., 2007).
T671 59747-59961 Sentence denotes Similarly, CD8+ T cell exhaustion is well known during persistent human immunodeficiency virus (HIV) infection, marked by robust expression of exhaustion markers like PD-1 (Day et al., 2006; Petrovas et al., 2006).
T672 59962-60135 Sentence denotes Following exhaustion, these cells are eliminated from the circulation, which is responsible for the decline in their number with long-term infection (Petrovas et al., 2009).
T673 60136-60425 Sentence denotes In addition to transcriptional changes that lead to exhaustion during chronic viral infection, the presence of secretory inhibitory molecules has been implicated in lymphocyte exhaustion with a prominent role of IL-10 and TGF-β in CD8+ T cell exhaustion (Wherry, 2011; Blank et al., 2019).
T674 60426-60581 Sentence denotes Increased levels of these cytokines in COVID-19 patients may also suggest their potential role in CD8+ T cell exhaustion (Chen, 2020; Liu A. et al., 2020).
T675 60582-60743 Sentence denotes Furthermore, severe COVID-19 patients had elevated lactic acid levels which is a known inhibitor of T cell function (Fischer et al., 2007; Tan L. et al., 2020b).
T676 60744-60836 Sentence denotes Another vital aspect of lymphocytopenia is direct cell death by the virus during infections.
T677 60837-60979 Sentence denotes HIV is a well-known example wherein CD4+ T cells undergo activation-induced cell death by the virus (Day et al., 2006; Petrovas et al., 2009).
T678 60980-61111 Sentence denotes Though respiratory viruses are not known to induce T cell apoptosis directly, virus-activated secondary factors may be responsible.
T679 61112-61267 Sentence denotes For example, T cell apoptosis was seen by the enhanced expression of death receptors during the infection of influenza virus (H5N1) (Boonnak et al., 2014).
T680 61268-61474 Sentence denotes MERS infection was also associated with T cell apoptosis by the virus-mediated activation of intrinsic and extrinsic pathways of cell death, resulting in their depletion from circulation (Chu et al., 2014).
T681 61475-61577 Sentence denotes The MERS infection was abortive in these cells, suggesting indirect activation of cell death pathways.
T682 61578-61741 Sentence denotes A few in vitro studies have shown low replication of SARS-CoV in T cells and the absence of any significant cell death (Chan and Chen, 2008; Wang X. et al., 2020).
T683 61742-61939 Sentence denotes Whether SARS-CoV-2 infects, T cells are currently unknown, but it appears that T cell decline during COVID-19 cannot be attributed to direct cell death by the virus but to the exhaustion mechanism.
T684 61940-62296 Sentence denotes In addition to the mechanism mentioned above associated with lymphocytopenia, secondary signaling mediated via engagement of death receptors, increased ROS, HMGB1 and other death-inducing agents released by the infected and damaged ATII cells may also be implicated in T cell decline (Kaminskyy and Zhivotovsky, 2010; Juno et al., 2017; Zhan et al., 2017).
T685 62297-62508 Sentence denotes Thus, based on these early findings, lymphocyte exhaustion may be driven by multiple factors that actively engage in rendering these cells ineffective, followed by their subsequent elimination (lymphocytopenia).
T686 62509-62641 Sentence denotes Overall, a clear picture is emerging, which strongly indicates lymphocytopenia as a predictive marker for COVID-19 disease severity.
T687 62642-62861 Sentence denotes Along with increased neutrophil number, the blood lymphocyte count serves as a better prognostic marker and reflects the immunopathological state of the patients (Giamarellos-Bourboulis et al., 2020; Liu et al., 2020b).
T688 62862-62991 Sentence denotes Further, based on these emerging studies, it is becoming evident that T cell response is heterogeneous during COVID-19 infection.
T689 62992-63212 Sentence denotes While peripheral blood may exhibit lymphocytopenia, and mostly exhausted status of these cells, the site of infection is associated with an activated profile of the cells and hence determines the severity of the disease.
T690 63213-63302 Sentence denotes Thus, caution should be exercised while designing therapeutic interventions for COVID-19.
T691 63303-63394 Sentence denotes The underlying immunological state should be borne in mind while considering the treatment.
T692 63395-63612 Sentence denotes Patients with lymphocytopenia and elevated functional and activation status of T cells may benefit from immunomodulatory approaches like mesenchymal stem cells, which are currently under clinical trials (NCT04377334).
T693 63613-63832 Sentence denotes Patients with imperfect T cell and B cell responses may benefit from convalescent plasma therapy, whereas patients with impaired interferon response may respond better to interferon therapies (NCT04350671; NCT04388709).
T694 63833-63999 Sentence denotes Thus, before a vaccine is available, a rational way to recommend therapy for severe cases of COVID-19 should be based on the patient’s underlying immunological state.
T695 64000-64111 Sentence denotes However, the treatment options become challenging when the patients exhibit cytokine storm and associated ARDS.
T696 64112-64315 Sentence denotes Moreover, it is imperative to analyze the T and B cell response by considering the age of the patient, comorbid condition, severity score, time of sample collection, and the method used for the analysis.
T697 64316-64526 Sentence denotes Because, the adaptive immune response is highly sensitive to these factors, and undermining them may thus further complicate our understanding of the development of the immunopathological state during COVID-19.