| Id |
Subject |
Object |
Predicate |
Lexical cue |
| T433 |
0-38 |
Sentence |
denotes |
Dysfunctional Adaptive Immune Response |
| T434 |
39-113 |
Sentence |
denotes |
A subset of COVID-19 patients displays robust activation of T and B cells. |
| T435 |
114-279 |
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 |
280-514 |
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 |
515-697 |
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 |
698-948 |
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 |
950-1011 |
Sentence |
denotes |
Proinflammatory Cytokines Secreted by T Cells During COVID-19 |
| T440 |
1012-1175 |
Sentence |
denotes |
Hyperinflammatory condition mediated by cytokines, chemokines and associated proinflammatory molecules which are secreted by both innate and adaptive immune cells. |
| T441 |
1176-1362 |
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 |
1363-1568 |
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 |
1569-1699 |
Sentence |
denotes |
In comparison to the mild cases (n = 19), patients with severe disease (n = 10) condition had increased levels of these cytokines. |
| T444 |
1700-1819 |
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 |
1820-2003 |
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 |
2004-2304 |
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 |
2305-2446 |
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 |
2447-2594 |
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 |
2595-2892 |
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 |
2893-2994 |
Sentence |
denotes |
These studies thus suggest a robust activation of TH1 specific and CD8+ T cells in COVID-19 patients. |
| T451 |
2995-3107 |
Sentence |
denotes |
On the contrary, there are studies which show decreased cytokine expression by T cells in severe COVID-19 cases. |
| T452 |
3108-3238 |
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 |
3239-3335 |
Sentence |
denotes |
Similarly, a decrease in IL-2+ CD8+ and IFN-γ+ CD8+ cells was also observed (Diao et al., 2020). |
| T454 |
3336-3627 |
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 |
3628-3857 |
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 |
3858-4032 |
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 |
4033-4363 |
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 |
4365-4434 |
Sentence |
denotes |
Activation and Exhaustion Status of T Cells During COVID-19 Infection |
| T459 |
4435-4570 |
Sentence |
denotes |
The activation, exhaustion, and proliferation response of T and B cells are considered an integral determinant of the disease severity. |
| T460 |
4571-4842 |
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 |
4843-4958 |
Sentence |
denotes |
However, contradictory reports exist regarding the functional and exhaustion status of these cells during COVID-19. |
| T462 |
4959-5167 |
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 |
5168-5327 |
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 |
5328-5415 |
Sentence |
denotes |
However, the major limitation of this study was that only a single patient was studied. |
| T465 |
5416-5554 |
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 |
5555-5734 |
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 |
5735-5929 |
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 |
5930-6045 |
Sentence |
denotes |
Similarly, a subset of severe cases had increased Ki-67 expressing CD4+ and CD8+ T cells, displaying proliferation. |
| T469 |
6046-6238 |
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 |
6239-6408 |
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 |
6409-6567 |
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 |
6568-6678 |
Sentence |
denotes |
The study found activated status of CD4+ and CD8+ T cells as revealed by an increase in CD38+HLA-D population. |
| T473 |
6679-6821 |
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 |
6822-7000 |
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 |
7001-7143 |
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 |
7144-7300 |
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 |
7301-7466 |
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 |
7467-7594 |
Sentence |
denotes |
While across studies, it has become apparent that T cells show robust activation status in severe cases than mild and moderate. |
| T479 |
7595-7698 |
Sentence |
denotes |
These cells also exhibit exhaustion status, which may occur concomitantly with their activation status. |
| T480 |
7699-7922 |
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 |
7923-8048 |
Sentence |
denotes |
Further, these cells were also associated with concomitant expression of proliferation (Ki-67) and exhaustion (PD-1) markers. |
| T482 |
8049-8247 |
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 |
8248-8402 |
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 |
8403-8630 |
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 |
8631-8870 |
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 |
8871-8949 |
Sentence |
denotes |
The exhaustion was more pronounced in severe cases (n = 9) than mild (n = 20). |
| T487 |
8950-9055 |
Sentence |
denotes |
However, both these studies did not consider the age of the patients when comparing the disease severity. |
| T488 |
9056-9173 |
Sentence |
denotes |
Further, the study did not consider the temporal dynamics of these cells while measuring their functional properties. |
| T489 |
9174-9385 |
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 |
9386-9485 |
Sentence |
denotes |
While IL-2 expressing CD4+ T cell population was also significantly lower in healthy vs mild group. |
| T491 |
9486-9666 |
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 |
9667-9779 |
Sentence |
denotes |
Exhaustive states of both CD4+ and CD8+ T cells were also present in patients requiring ICU (Diao et al., 2020). |
| T493 |
9780-9911 |
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 |
9912-10254 |
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 |
10255-10353 |
Sentence |
denotes |
More studies are necessary before using such an approach can be used for therapeutic intervention. |
| T496 |
10354-10473 |
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 |
10474-10643 |
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 |
10644-10757 |
Sentence |
denotes |
This increase in infiltration of these cells was concomitantly associated with their decline in peripheral blood. |
| T499 |
10758-10871 |
Sentence |
denotes |
Others presented a similar activation profile of CD8+ T cells (Kuri-Cervantes et al., 2020; Mathew et al., 2020). |
| T500 |
10872-11217 |
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 |
11218-11416 |
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 |
11417-11579 |
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 |
11580-11717 |
Sentence |
denotes |
These activated T cells are further recruited at the sites of infection (initially lungs) in the presence of their respective chemokines. |
| T504 |
11718-11935 |
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 |
11936-12264 |
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 |
12265-12531 |
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 |
12532-12904 |
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 |
12905-12983 |
Sentence |
denotes |
Exhaustive state of B cells is reflected by a decrease in antibody production. |
| T509 |
12984-13173 |
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 |
13174-13382 |
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 |
13383-13499 |
Sentence |
denotes |
While comparing the response with Influenza A viruses, SARS-CoV-2 directed CD8+ T exhibit relatively lower response. |
| T512 |
13500-13842 |
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 |
13843-13963 |
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 |
13964-14193 |
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 |
14194-14275 |
Sentence |
denotes |
Both CD4+ and CD8+ T cells also exhibit dysregulated response (Qin et al., 2020). |
| T516 |
14276-14394 |
Sentence |
denotes |
Decreased levels of CD4+ regulatory cells as marked by CD3+ CD4+ CD25+ CD127low+ population was found in severe cases. |
| T517 |
14395-14492 |
Sentence |
denotes |
Similarly, the study found decreased CD8+ suppressor T cells (CD3+, CD8+, CD28+) in severe cases. |
| T518 |
14493-14721 |
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 |
14723-14763 |
Sentence |
denotes |
Impaired B Cell Response During COVID-19 |
| T520 |
14764-14888 |
Sentence |
denotes |
Regulated and controlled B cell response is critical for the effective immune response against the CoVs, as discussed above. |
| T521 |
14889-15006 |
Sentence |
denotes |
However, under certain conditions, B cell response may be detrimental and aggravate the underlying disease condition. |
| T522 |
15007-15194 |
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 |
15195-15380 |
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 |
15381-15493 |
Sentence |
denotes |
These cells express proliferation (Ki67+), differentiation (CD27+ CD38+), as well as exhaustion markers (PD-1+). |
| T525 |
15494-15661 |
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 |
15662-15816 |
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 |
15817-15988 |
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 |
15989-16085 |
Sentence |
denotes |
However, how this activated status of B cells had an impact on disease severity was not studied. |
| T529 |
16086-16306 |
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 |
16307-16548 |
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 |
16549-16767 |
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 |
16768-16978 |
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 |
16979-17066 |
Sentence |
denotes |
The ASCs were identified as the population of cells with CD138+ and CD21low expression. |
| T534 |
17067-17155 |
Sentence |
denotes |
However, no comparison was drawn between various age groups concerning disease severity. |
| T535 |
17156-17292 |
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 |
17293-17433 |
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 |
17434-17541 |
Sentence |
denotes |
A recent study has provided mechanistic insights into how some cases of COVID-19 exhibit low B cell number. |
| T538 |
17542-17770 |
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 |
17771-17919 |
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 |
17920-17998 |
Sentence |
denotes |
Further, an increase in expression of TNF-α levels was found in the follicles. |
| T541 |
17999-18231 |
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 |
18232-18405 |
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 |
18406-18702 |
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 |
18703-18797 |
Sentence |
denotes |
Thus, this study provides a probable cause for the B cell decline in severe cases of Covid-19. |
| T545 |
18798-18969 |
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 |
18970-19055 |
Sentence |
denotes |
Thus, the effect of age on the decline in B cells cannot be undermined in this study. |
| T547 |
19056-19255 |
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 |
19257-19286 |
Sentence |
denotes |
Antibody Dynamics in COVID-19 |
| T549 |
19287-19425 |
Sentence |
denotes |
Antibody-based therapy is being considered as a potential intervention for COVID-19, owing to the successful preliminary results with CPT. |
| T550 |
19426-19604 |
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 |
19605-19823 |
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 |
19824-20053 |
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 |
20054-20250 |
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 |
20251-20516 |
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 |
20517-20680 |
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 |
20681-20805 |
Sentence |
denotes |
Zheng M. et al. (2020) showed the presence of RBD-specific IgG and IgA antibodies in patients with severe disease condition. |
| T557 |
20806-20881 |
Sentence |
denotes |
The study included 13 severe and 41 non-severe cases of various age groups. |
| T558 |
20882-21041 |
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 |
21042-21210 |
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 |
21211-21338 |
Sentence |
denotes |
This study provided a direct relation of inflammatory response with humoral immune response in context to the disease severity. |
| T561 |
21339-21441 |
Sentence |
denotes |
However, the antigen-neutralizing property of these SARS-CoV-2 specific antibodies was not determined. |
| T562 |
21442-21625 |
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 |
21626-21758 |
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 |
21759-21911 |
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 |
21912-21991 |
Sentence |
denotes |
Antibody titer was higher in the critical patients as compared to non-critical. |
| T566 |
21992-22205 |
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 |
22206-22303 |
Sentence |
denotes |
However, like other studies, this study also suffers from the same limitation of low sample size. |
| T568 |
22304-22518 |
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 |
22519-22707 |
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 |
22708-22876 |
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 |
22877-23066 |
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 |
23067-23215 |
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 |
23216-23461 |
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 |
23462-23594 |
Sentence |
denotes |
Further, the antibody titer was significantly higher in the deceased patients with faster production than in the recovered patients. |
| T575 |
23595-23786 |
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 |
23787-23956 |
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 |
23957-24154 |
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 |
24155-24321 |
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 |
24322-24453 |
Sentence |
denotes |
However, since mechanistic details are difficult to discern in clinical samples, more studies in animal models need to be explored. |
| T580 |
24454-24743 |
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 |
24744-24873 |
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 |
24874-25028 |
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 |
25029-25230 |
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 |
25231-25344 |
Sentence |
denotes |
Further, the viral shedding in the asymptomatic group was higher than the symptomatic group (Long et al., 2020b). |
| T585 |
25345-25547 |
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 |
25548-25669 |
Sentence |
denotes |
The authors found a significant decline in IgG antibodies in the sera of convalescent patients with mostly mild symptoms. |
| T587 |
25670-25835 |
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 |
25836-25987 |
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 |
25988-26316 |
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 |
26317-26455 |
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 |
26456-26607 |
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 |
26608-26842 |
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 |
26843-26976 |
Sentence |
denotes |
This dynamic antibody response is critical while considering convalescent plasma therapy (CPT) for severe or critically ill patients. |
| T594 |
26977-27109 |
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 |
27110-27253 |
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 |
27254-27569 |
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 |
27571-27635 |
Sentence |
denotes |
SARS-CoV-2 Antibody Cross-Reactivity and Neutralization Property |
| T598 |
27636-27720 |
Sentence |
denotes |
A range of SARS-CoV specific antibodies have shown cross-reactivity with SARS-CoV-2. |
| T599 |
27721-27805 |
Sentence |
denotes |
These antibodies target S protein and mostly the RBD region (Hoffmann et al., 2020). |
| T600 |
27806-27954 |
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 |
27955-28211 |
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 |
28212-28329 |
Sentence |
denotes |
Thus, the cross-reactive nature of some of these antibodies may ensure their efficacy against multiple coronaviruses. |
| T603 |
28330-28472 |
Sentence |
denotes |
However, at the same time, these cross-reactive antibodies should also have neutralizing property; otherwise, they will have a harmful effect. |
| T604 |
28473-28597 |
Sentence |
denotes |
A recent study explored the cross-reactive and neutralization property of these antibodies simultaneously (Lv et al., 2020). |
| T605 |
28598-28804 |
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 |
28805-28886 |
Sentence |
denotes |
These results were further confirmed in animal models of SARS-CoV-2 and SARS-CoV. |
| T607 |
28887-29065 |
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 |
29066-29264 |
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 |
29265-29491 |
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 |
29492-29574 |
Sentence |
denotes |
These factors also become essential while considering convalescent plasma therapy. |
| T611 |
29575-29692 |
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 |
29693-29817 |
Sentence |
denotes |
The study led to the identification of 14 neutralizing antibodies, among which one (BD-368-2) showed the most potent effect. |
| T613 |
29818-29948 |
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 |
29949-30189 |
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 |
30190-30346 |
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 |
30348-30390 |
Sentence |
denotes |
Antibody Dependent Enhancement in COVID-19 |
| T617 |
30391-30501 |
Sentence |
denotes |
Non-neutralizing but cross-reactive antibodies may lead to ADE and hence enhance the immunopathological state. |
| T618 |
30502-30747 |
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 |
30748-30953 |
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 |
30954-31151 |
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 |
31152-31247 |
Sentence |
denotes |
In vitro studies on monocytes and macrophages have shown ADE in SARS-CoV (Flipse et al., 2016). |
| T622 |
31248-31375 |
Sentence |
denotes |
However, no definitive clinical data is available that indicates the occurrence of ADE during SARS-CoV or SARS-CoV-2 infection. |
| T623 |
31376-31598 |
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 |
31600-31634 |
Sentence |
denotes |
Unconventional T Cells in COVID-19 |
| T625 |
31635-31789 |
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 |
31790-31865 |
Sentence |
denotes |
This increase in NKT cells was similarly reflected in the peripheral blood. |
| T627 |
31866-31953 |
Sentence |
denotes |
Conversely, a decline in the number of these cells was found during the recovery phase. |
| T628 |
31954-32151 |
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 |
32152-32314 |
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 |
32315-32443 |
Sentence |
denotes |
However, no direct correlation of these cells types with disease severity was found, probably due to meagre sample size (n = 3). |
| T631 |
32444-32614 |
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 |
32615-32918 |
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 |
32919-33125 |
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 |
33126-33401 |
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 |
33402-33561 |
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 |
33562-33719 |
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 |
33720-33955 |
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 |
33957-33988 |
Sentence |
denotes |
Lymphocytopenia During COVID-19 |
| T639 |
33989-34265 |
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 |
34266-34392 |
Sentence |
denotes |
Interestingly, restoration in the lymphocyte count is also consistently seen during the recovery phase (Chen Y. et al., 2020). |
| T641 |
34393-34529 |
Sentence |
denotes |
Based on these early findings, lymphocytopenia is considered a predictive indicator of COVID-19 disease severity (Tan L. et al., 2020b). |
| T642 |
34530-34748 |
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 |
34749-35077 |
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 |
35078-35264 |
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 |
35265-35377 |
Sentence |
denotes |
Chemokines and cytokines responsible for CD8+ T cells priming and chemotaxis were also detected in the patients. |
| T646 |
35378-35608 |
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 |
35609-35836 |
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 |
35837-35975 |
Sentence |
denotes |
The decline in the number of these cells can attribute to their concomitant migration to the infected regions under inflammatory response. |
| T649 |
35976-36170 |
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 |
36171-36327 |
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 |
36328-36430 |
Sentence |
denotes |
A single patient analysis revealed increased CD4+ and CD8+ T cells in the BALF (Voiriot et al., 2020). |
| T652 |
36431-36642 |
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 |
36643-36919 |
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 |
36920-37074 |
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 |
37075-37244 |
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 |
37245-37440 |
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 |
37441-37631 |
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 |
37632-37907 |
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 |
37908-38024 |
Sentence |
denotes |
Similarly, CD8+ T cell exhaustion is determined by reduced expression of IL-2, IFN-γ, TNF-α, and cytolytic granules. |
| T660 |
38025-38286 |
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 |
38287-38511 |
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 |
38512-38640 |
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 |
38641-38838 |
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 |
38839-38986 |
Sentence |
denotes |
Moreover, increased expression of exhaustion-related genes like BATF, IRF4, and CD274 also correlated with disease severity (Hadjadj et al., 2020). |
| T665 |
38987-39104 |
Sentence |
denotes |
Interestingly, increased apoptosis of T cells became evident in severe cases as compared to mild/moderate conditions. |
| T666 |
39105-39249 |
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 |
39250-39458 |
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 |
39459-39673 |
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 |
39674-39852 |
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 |
39853-40035 |
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 |
40036-40250 |
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 |
40251-40424 |
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 |
40425-40714 |
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 |
40715-40870 |
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 |
40871-41032 |
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 |
41033-41125 |
Sentence |
denotes |
Another vital aspect of lymphocytopenia is direct cell death by the virus during infections. |
| T677 |
41126-41268 |
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 |
41269-41400 |
Sentence |
denotes |
Though respiratory viruses are not known to induce T cell apoptosis directly, virus-activated secondary factors may be responsible. |
| T679 |
41401-41556 |
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 |
41557-41763 |
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 |
41764-41866 |
Sentence |
denotes |
The MERS infection was abortive in these cells, suggesting indirect activation of cell death pathways. |
| T682 |
41867-42030 |
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 |
42031-42228 |
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 |
42229-42585 |
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 |
42586-42797 |
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 |
42798-42930 |
Sentence |
denotes |
Overall, a clear picture is emerging, which strongly indicates lymphocytopenia as a predictive marker for COVID-19 disease severity. |
| T687 |
42931-43150 |
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 |
43151-43280 |
Sentence |
denotes |
Further, based on these emerging studies, it is becoming evident that T cell response is heterogeneous during COVID-19 infection. |
| T689 |
43281-43501 |
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 |
43502-43591 |
Sentence |
denotes |
Thus, caution should be exercised while designing therapeutic interventions for COVID-19. |
| T691 |
43592-43683 |
Sentence |
denotes |
The underlying immunological state should be borne in mind while considering the treatment. |
| T692 |
43684-43901 |
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 |
43902-44121 |
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 |
44122-44288 |
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 |
44289-44400 |
Sentence |
denotes |
However, the treatment options become challenging when the patients exhibit cytokine storm and associated ARDS. |
| T696 |
44401-44604 |
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 |
44605-44815 |
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. |
