LitCovid-sentences  

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Id Subject Object Predicate Lexical cue
T167 0-34 Sentence denotes Immune Response Against SARS-CoV-2
T168 36-50 Sentence denotes Cytokine Storm
T169 51-426 Sentence denotes Antiviral immune response is usually coordinated by IFN-type cytokines that activate cells and intensify the response against these invading agents, triggered by the recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs), such as toll-like receptors (TLR), fundamental for pathogen recognition and activation of innate immunity.
T170 427-577 Sentence denotes Type 7 of TLR (TLR7) – expressed on the surface of endosomes predominantly in the lungs, placenta, and spleen – might play a central role in COVID-19.
T171 578-790 Sentence denotes This receptor has been reported to quickly recognize single-stranded SARS-CoV-1 RNA, inducing the production of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-12 in plasmacytoid dendritic cells (141–143).
T172 791-947 Sentence denotes The recognition of SARS-CoV-2 RNA by TLR7 can mediate the release of cytokines in response to the virus, a context in which IL-6 may play an important role.
T173 948-1196 Sentence denotes It has been well described that IL-6 is a pleiotropic cytokine with distinct functions in different contexts in the immune system, being fundamental for the formation of follicular T helper lymphocytes and the generation of long-lived plasma cells.
T174 1197-1535 Sentence denotes However, this cytokine can also inhibit the activity of CD8+ cytotoxic lymphocytes by inducing the expression of PD1 in these cells, in addition to inhibiting suppressors of cytokine signaling 3 (SOCS3), an important protein responsible for controlling cytokine production, leading to an excessive release of inflammatory mediators (144).
T175 1536-1859 Sentence denotes The pathophysiology of COVID-19 is yet to be fully elucidated and several gaps still need to be filled, however, several studies have shown an increase in cytokines, notably pro-inflammatory, in the serum of infected patients, which has been associated with hyper inflammation and the lung injury particular to the disease.
T176 1860-2145 Sentence denotes The main cytokines described include TNF-α, IFN-γ, IL-1β, IL-1Ra, IL-2R, IL-6, IL-7, IL-8, IL-9, IL-10, basic FGF, G-CSF, GM-CSF, IP-10, MCP-1, MIP-1a, PD6F, and VEGF, in addition to an increase in other inflammation biomarkers, such as C-reactive protein, ferritin, and procalcitonin.
T177 2146-2272 Sentence denotes However, mediators related to the complement system, such as C3 and C4, did not present any difference in healthy individuals.
T178 2273-2627 Sentence denotes Furthermore, even higher levels of these mediators were found in patients of critical COVID-19 cases, suggesting that the severity of the disease may be associated with this huge amount of inflammatory mediators, called cytokine storm, which overloads the immune system with information, preventing the establishment of an effective immune response (26).
T179 2628-3089 Sentence denotes For example, a study published by Valle et al. showed that COVID-19 patients have higher levels of IL-6, IL-8, and TNF-alpha than healthy individuals on hospital admission; moreover, when they stratified the population by low versus high cytokine levels and applied a risk competition model, it was found that each cytokine is an independent predictive factor of the patients’ overall survival and is significantly associated with worse clinical outcomes (145).
T180 3090-3302 Sentence denotes On the other hand, in theory, a type I IFN-mediated response activates the JAK-STAT signaling pathway that should be able to suppress viral replication and prevent the virus from spreading early in the infection.
T181 3303-3428 Sentence denotes This is probably what occurs in asymptomatic individuals who can establish an effective response against SARS-CoV-2 (9, 141).
T182 3429-3603 Sentence denotes However, in several viruses, viral proteins can modulate the production of this type of IFN, impairing the generation of an effective antiviral response (141, 143, 146, 147).
T183 3604-3925 Sentence denotes Li et al. (148) conducted an in vitro experiment that revealed a strong capacity of ORF6, ORF8, and nucleocapsid proteins of SARS-CoV-2 to inhibit IFN-β and NF-κB activity, in addition to genes containing interferon-stimulated response elements (ISREs), suggesting that the virus has an important IFN antagonist activity.
T184 3926-4152 Sentence denotes By monitoring the production of type I IFN in SARS-CoV-2-positive patients, Trouillet-Assant et al. (149) found a peak in IFN-α2 production between 8 and 10 days after the onset of symptoms, in general, which reduces overtime.
T185 4153-4332 Sentence denotes However, as many as one critically ill patient in five was unable to produce any amount of type I IFN and had a higher viral load, respiratory failure, and worse clinical outcome.
T186 4333-4574 Sentence denotes Nonetheless, Zhou et al. (150) conducted a study that demonstrated that SARS-CoV-2 infection induced a markedly elevated expression of IFN-related inflammatory genes, which appears to decrease over time in mild cases, but not in severe ones.
T187 4575-4691 Sentence denotes Additionally, Major et al. (151) described the role of types I and III of IFN in lung repair during viral infection.
T188 4692-4913 Sentence denotes The production of IFN-α/β and IFN-λ in C57BL/6 mice was detected immediately at the early stage of influenza virus infection and decreased over time, having reached undetectable levels at the onset of epithelial recovery.
T189 4914-5161 Sentence denotes Interestingly, the treatment with IFN-α, β, or λ during the recovery phase reduced the proliferation type II alveolar epithelial cells by activation of IFN-induced p53, aggravating lung injury, disease severity, and susceptibility to coinfections.
T190 5162-5319 Sentence denotes Therefore, time and duration of IFN are critical factors for viral infection response and should be thoroughly considered as a COVID-19 therapeutic strategy.
T191 5320-5608 Sentence denotes Similarly, an experimental study conducted with MERS patients indicated that type I IFN has protective activity against this infection and the blockade of its signaling resulted in delayed virus clearance, enhanced neutrophil infiltration, and impaired MERS-CoV–specific T cell responses.
T192 5609-5697 Sentence denotes Additionally, early treatment using this type of IFN prevented fatal infections in mice.
T193 5698-6091 Sentence denotes However, the late treatment did not cure the animals and failed to effectively inhibit virus replication, increased infiltration, and activation of monocytes, macrophages, and neutrophils in the lungs, in addition to having enhanced proinflammatory cytokine expression, which led to fatal pneumonia, indicating that type I IFN plays a central role at the very beginning of the infection (152).
T194 6092-6254 Sentence denotes Therefore, using IFN in SARS-CoV-2 treatment seems to be beneficial at the early infection stage, especially for patients unable to produce this type of response.
T195 6255-6434 Sentence denotes Furthermore, as the disease progresses, the use of inflammatory cytokine blockers for patients who fail at regulating their production over time could represent a better strategy.
T196 6435-6708 Sentence denotes COVID-19 patients also have high levels of production of anti-inflammatory cytokines, such as IL-10, perhaps as a way of compensating for the exacerbated inflammatory response, which can lead to a picture of immune dissonance and anergy towards the infection (26, 153–155).
T197 6709-6937 Sentence denotes It is fundamental to perform further studies that elucidate the mechanisms of the immune response and the balance between pro-inflammatory and anti-inflammatory response patterns to understand the immunopathogenesis of COVID-19.
T198 6938-7057 Sentence denotes IL-7 is a pleiotropic cytokine that plays an essential role in the differentiation and clonal expansion of lymphocytes.
T199 7058-7384 Sentence denotes Chi et al. (156) described the production of IL-7 in COVID-19 patients; when compared to healthy controls, both asymptomatic and symptomatic individuals in the acute phase show an increase in the levels of this cytokine, however convalescent individuals return to the basal state equal to that observed in healthy individuals.
T200 7385-7539 Sentence denotes When symptomatic individuals were stratified according to the severity of the disease, those with moderate to severe conditions had higher levels of IL-7.
T201 7540-7806 Sentence denotes In addition, SARS-CoV-2-specific T cells from the peripheral blood of convalescent individuals of COVID-19 show high expressions of CD127, a receptor necessary for homeostatic cell proliferation triggered by IL-7, which may be related to the recovery observed (157).
T202 7807-7958 Sentence denotes Patients with a severe COVID-19 condition, on the other hand, have an increased IL-7 production, but contradictorily they also have severe lymphopenia.
T203 7959-8163 Sentence denotes Thus, we speculate that the deficiency in the expression of CD127 might occur in severely ill patients, which culminates in the deficiency of cell proliferation induced by IL-7 and consequent lymphopenia.
T204 8164-8288 Sentence denotes However, studies that seek to evaluate the expression profile of IL-7 and CD127 in COVID-19 patients need to be carried out.
T205 8289-8404 Sentence denotes In addition, the use of IL-7 as a treatment for COVID-19 patients has been evaluated and will be discussed further.
T206 8405-8538 Sentence denotes Several pro-inflammatory cytokines have been described in COVID-19 patients and are associated with the disease’s immunopathogenesis.
T207 8539-8630 Sentence denotes Among them, IL-1β and TNF-α stand out for playing a central role in this context (26, 156).
T208 8631-9025 Sentence denotes The respiratory failure characteristic of SARS-CoV-2 infection, especially in individuals who develop the most severe forms of the disease, occurs independently of infection or viral replication in the epithelial bronchial cells and probably occurs due to exacerbated inflammatory dysregulation, resulting from activation of the NLRP3 inflammasome pathway and consequent release of IL-1β (158).
T209 9026-9308 Sentence denotes However, although several articles have shown an increase in IL-1β production in COVID-19 patients and early treatment with IL-1 receptor blockers has helped prevent respiratory failure (159), its exact role in the immunopathogenesis of the disease has not yet been fully described.
T210 9309-9382 Sentence denotes Cytokine storms may have great relevance in the pathogenesis of COVID-19.
T211 9383-9503 Sentence denotes The induction of inflammatory mediators can induce cell damage, especially in lung tissues, causing respiratory failure.
T212 9504-9736 Sentence denotes In addition, several of these mediators have potent vasodilator activity, which at the local level can cause pulmonary edemas, while at the systemic level leads to septic shock, worsening the clinical condition of these individuals.
T213 9737-10053 Sentence denotes Similarly, several studies have shown that viral infections can induce cytokine storms, or take advantage of it, to establish infection and escape from the immune system, intensifying pathological phenomena such as those observed in sepsis, in addition to increasing the mortality rate of this population (160, 161).
T214 10054-10351 Sentence denotes Despite the absence of direct evidence of the role of cytokines and chemokines in lung injury, initial studies have shown that the increase in these pro-inflammatory mediators is associated with lung injury in patients with COVID-19 and has a central role in the pathogenesis of the disease (153).
T215 10352-10585 Sentence denotes The balance of the innate immune response is essential at the beginning of the infection, while its imbalance can culminate in excessive inflammation, which hinders the establishment of an effective immune response against the virus.
T216 10586-10906 Sentence denotes Therefore, using hemoperfusion can be an important tool to treat severe COVID-19 patients who developed cytokine storms, as well as other treatments focusing on controlling and reducing hyper inflammation using specific blockers or monoclonal antibodies directed against the mediator or to antagonize its receptor (144).
T217 10908-10930 Sentence denotes Innate Immune Response
T218 10931-11112 Sentence denotes The innate immune system is the first line of defense against pathogens through the activation of PRR in macrophages, neutrophils, and dendritic cells by the interaction with PAMPs.
T219 11113-11333 Sentence denotes An effective innate immune response against viruses like SARS-CoV-2 is essential not only to initiate the response but also to structure the basis for the production of a robust and more specific adaptive response (162).
T220 11334-11465 Sentence denotes Changes in this process, commonly observed in viral infections, can cause an immune imbalance and susceptibility of the host (163).
T221 11466-11635 Sentence denotes Patients who develop severe COVID-19 exhibited a marked increase in neutrophil and reduced lymphocytes counts compared with patients with mild signs of the disease (10).
T222 11636-11860 Sentence denotes A general increase in the number of circulating neutrophils and the reduction of lymphocytes enhance the neutrophil/lymphocyte ratio, which has been used as a predictor of the infection severity and development of pneumonia.
T223 11861-12008 Sentence denotes In addition to being a predictor of a worse prognosis, an increase in this ratio also indicates a serious immune imbalance in these patients (153).
T224 12009-12290 Sentence denotes In addition to having high levels of cell-free DNA, myeloperoxidase-DNA, and citrullinated histone H3 – important markers of neutrophil extracellular traps (NETs) –, the serum of COVID-19-positive patients was able to strongly trigger NETosis in healthy neutrophils in vitro (164).
T225 12291-12580 Sentence denotes Despite representing important strategies to eliminate pathogens by neutrophils, NETs damage healthy tissue and induce inflammation (165), in addition to featuring a variety of oxidizing agents and being involved in several vascular diseases, as well as pathogen-induced acute lung injury.
T226 12581-12830 Sentence denotes The release of NETs by neutrophils can be triggered by several factors, such as virus-damaged epithelial cells, activated platelets, activated endothelial cells, and inflammatory cytokines, such as IL-1β, IL-8, and G-CSF, among others (95, 166–169).
T227 12831-12971 Sentence denotes In this context, it is fundamental to conduct studies assessing the role of neutrophils and NETs to better understand COVID-19 pathogenesis.
T228 12972-13147 Sentence denotes Concerning monocytes, COVID-19 patients have shown an abundant circulation of CD14+ CD16+ cells, with a sharper increase in patients who developed severe respiratory syndrome.
T229 13148-13343 Sentence denotes This subtype of monocytes can over-secrete TNF-α, IL-1β, and IL-6 and expand quickly in systemic infections, implying that they must play an important role in the rapid defense against pathogens.
T230 13344-13478 Sentence denotes Controversially, these cells are the main producers of IL-10, which makes their exact function in immune responses elusive (170, 171).
T231 13479-13695 Sentence denotes Additionally, Dutertre et al. (172) demonstrated that CD14+ CD16+ monocytes are responsible for TNF overproduction in HIV infections and might be considered the major actor in immune hyperactivation in disease (172).
T232 13696-13864 Sentence denotes A study assessing bronchoalveolar lavage of SARS-CoV-2-positive individuals found an abundance of monocytes-derived inflammatory macrophages in critically ill patients.
T233 13865-14084 Sentence denotes In addition, the authors observed through single-cell analysis that these macrophages can contribute to local inflammation by recruiting inflammatory monocytes and neutrophils through CCR1 and CXCR2 chemokine receptors.
T234 14085-14247 Sentence denotes However, in patients who presented a moderate form of the disease, macrophages produced chemo-attractants for the recruitment of T cells, such as CXCR3 and CXCR6.
T235 14248-14370 Sentence denotes Such a difference in response might be the key to understanding the pathogenesis of respiratory failure in COVID-19 (173).
T236 14371-14630 Sentence denotes Furthermore, critically ill patients have also manifested rapid proliferation of another subpopulation of monocytes characterized by GM-CSF+ IL-6+, which may be related to inflammatory risk and impairment of the lungs when migrating in large quantities (170).
T237 14631-14880 Sentence denotes GM-CSF has been described as an active part of the pathogenesis of autoimmune and inflammatory diseases, mainly in the involvement of myeloid cells, such as monocytes, which can initiate tissue damage in a dependent manner on this marker (174, 175).
T238 14881-15292 Sentence denotes In addition, high levels of mediators, such as IL-6, TNF-, and IL-10, found in these patients are likely to have been produced by these monocytes and to be highly involved in cytokine storm and pathogenesis of SARS-CoV-2, since as the disease progresses these mediators reduce, which is correlated to the restoration of the immune function of CD4+ and CD8+ T lymphocytes, which is further discussed later (154).
T239 15293-15494 Sentence denotes Critical COVID-19 patients have shown excessive activation of circulating HLA-DR- monocytes, which has been associated with the onset of respiratory failure, suggesting its role as a predictive factor.
T240 15495-15698 Sentence denotes The lack of expression of HLA-DR in monocytes may indicate a modulatory capacity of the virus, which prevents the antigen presentation and hampers the formation of an adaptive immune response (176, 177).
T241 15699-15921 Sentence denotes During an in vitro experiment, Yang et al. (178) found that, despite being permissive to infection by SARS-CoV-2, human monocyte-derived macrophages and dendritic cells are not able to effectively produce viral replicates.
T242 15922-16042 Sentence denotes Despite their central role in pathogenesis, this may indicate that these cells are not important reservoirs for viruses.
T243 16043-16283 Sentence denotes In addition, neither of the cell types developed a response based on type II IFN, but macrophages had lower production of type I and III IFN than the control, indicating that the virus can inhibit a response mediated by these types of IFNs.
T244 16284-16416 Sentence denotes Additionally, macrophages were able to trigger an exacerbated inflammatory response with higher TNF-α, IL-8, IP10, MIP1α, and IL-1β.
T245 16417-16568 Sentence denotes Dendritic cells had not been reported to show such inflammatory phenomenon, which is due to the ability of SARS-CoV-2 to inhibit STAT1 phosphorylation.
T246 16569-16805 Sentence denotes Such important attenuation of dendritic cell response caused by the virus may have important implications for humans to develop effective immunity, therefore, further studies should seek to better elucidate such a relevant relationship.
T247 16806-17218 Sentence denotes Similarly, in the presence of IFN-α and GM-CSF, circulating monocytes should quickly differentiate into monocyte-derived dendritic cells (mDC), which are important antigen-presenting cells capable of phagocyting viruses and initiating the adaptive immune response process, as well as activating CD4+ T cells, generating immune memory in the process, and refining the body’s defense against infections (179, 180).
T248 17219-17370 Sentence denotes The number of mDCs has not increased in patients infected with SARS-CoV-2 compared with healthy controls, even in the most severe cases of the disease.
T249 17371-17634 Sentence denotes Interestingly, the levels of GM-CSF in the serum of these patients are highly elevated, which should lead these cells to increase, demonstrating that the virus may have a mechanism to control the production of IFN-α and consequent differentiation of mDCs (9, 26).
T250 17635-17840 Sentence denotes In the same way, individuals infected and not infected with SARS-CoV-2 have similar levels of IL-12, an important cytokine produced by mDC that is involved in the differentiation of naïve T cells (9, 181).
T251 17841-18045 Sentence denotes Thus, we hypothesize that the lack of mDC generation and consequent inability of the infected individual to produce IL-12 may be among the main factors of innate immunity-related pathogenesis of COVID-19.
T252 18046-18297 Sentence denotes As further discussed, the increase in naïve T cells, reduced cell functionality of CD4+, CD8+, and natural killers (NK), and delay in the appearance of humoral response found in these patients indicates a failure in the generation and function of mDC.
T253 18298-18406 Sentence denotes Therefore, it is urgent to carry out studies aimed at analyzing the effect of SARS-CoV-2 on dendritic cells.
T254 18408-18422 Sentence denotes T Helper Cells
T255 18423-18541 Sentence denotes Establishing and maintaining immune response and memory generation against viruses depends on the activity of T cells.
T256 18542-18679 Sentence denotes These lymphocytes originate from bone marrow progenitor cells and migrate to the thymus for maturation, selection, and peripheral export.
T257 18680-18958 Sentence denotes Peripheral T cells are subdivided into groups that include naïve T cells, which are capable of responding to new antigens, memory T cells derived from previous antigen activations and maintain long-term immunity, and regulatory T cells that coordinate the immune response (163).
T258 18959-19319 Sentence denotes The immune response begins when naïve T cells encounter antigens and co-stimulatory molecules presented by antigen-presenting cells, such as dendritic cells that phagocytize the virus, resulting in the production of IL-2, proliferation, and differentiation of effector T cells, which migrate to various sites to promote the elimination of pathogens (163, 182).
T259 19320-19510 Sentence denotes Inflammatory factors induced by viruses can trigger a storm of mediators that cause changes in the differentiation and activation of T cells, disturbing the homeostasis of the immune system.
T260 19511-19730 Sentence denotes In patients with COVID-19, the overall percentage of T lymphocytes is generally reduced, especially CD4+ CD3+ T lymphocytes, which have an activation phenotype, a reduction much more pronounced in severely ill patients.
T261 19731-19892 Sentence denotes Furthermore, a higher percentage of CD4+ CD45RA+ naïve cells and lower CD4+ CD3+ CD45RO+ memory T cells were also found in COVID-19 patients (10, 153, 183, 184).
T262 19893-20039 Sentence denotes Polyfunctional CD4+ T cells are characterized by the expression of activation markers as well as their capacity to produce IFN-γ, IL-2, and TNF-α.
T263 20040-20184 Sentence denotes These cells have been linked to an excellent response against viral infections and during the development of immunity by vaccination (185, 186).
T264 20185-20552 Sentence denotes Even though COVID-19 patients have shown an increase in the expression of molecules related to T CD4+ activation, such as CD69, CD38, and CD44, molecules related to their function, such as intracellular IFN-γ, IL-2, and TNF-α, are reduced, especially in individuals with a more severe stage of the disease (9, 170), indicating an impairment of polyfunctional T cells.
T265 20553-20755 Sentence denotes Li et al. (187) demonstrated that patients infected with SARS-CoV-1 had elevated levels of polyfunctional CD4+ T cells, especially those in a severe condition but who progressed to clinical improvement.
T266 20756-21007 Sentence denotes In contrast, critically ill patients with SARS-CoV-2 demonstrated a drastic reduction of this cell subtype, which may indicate that this virus has developed its own mechanisms to control cellular responses, thus differing from other coronaviruses (9).
T267 21008-21242 Sentence denotes Similarly, Chen et al. (154) demonstrated that CD4+ T lymphocytes from COVID-19 patients showed increased expressions of T cell immunoglobulin-3 (Tim-3), a type I transmembrane protein that acts as a negative regulator of Th1 pattern.
T268 21243-21445 Sentence denotes CD4+ cells showed low expression of this marker at the early phase of infection, having progressively increased over time, indicating that the exhaustion of these cells occurs as the disease progresses.
T269 21446-21818 Sentence denotes Many studies with SARS-CoV-2 positive patients have described the generation of these exhausted pathological lymphocytes that exacerbate the inflammatory response at the early stage of infection, initiating a cytokine storm, followed by cell exhaustion and loss of functionality, a phenomenon that has appeared mainly in more severe cases of the disease (9, 10, 170, 188).
T270 21819-21957 Sentence denotes The vast majority of studies to date show impairment of proliferation, maturation, and response of T cells, especially in sicker patients.
T271 21958-22279 Sentence denotes This may indicate that SARS-CoV-2, similarly to other viral infections, can interfere with the function of CD4+ cells at the very beginning of the infection, causing excessive release of inflammatory mediators and exhaustion of the response capacity of these cells over time, reducing the host’s antiviral immunity (189).
T272 22280-22716 Sentence denotes What seems to happen in COVID-19 is that the total lymphocyte count is reduced in these patients and, among the remaining T cells, the highest percentage is from naïve CD4+ T lymphocytes, while the activated subpopulations, although few, present a phenotype with excess and reduced markers related to activation and function, respectively, indicating that, despite overactivation, these cells fail to exercise effective immune activity.
T273 22717-22825 Sentence denotes Another important point is the reduction of regulatory T cells CD4+ CD25+ Foxp3+ verified in these patients.
T274 22826-23089 Sentence denotes These cells have a fundamental role in the negative regulation of inflammation, control of cell proliferation, and the effector function of several cells, which probably has contributed to the excessive inflammation observed in critically ill patients (153, 190).
T275 23090-23357 Sentence denotes It has been described that regulatory T cells play a central role in mitigating the immune response in several viral infections (191); reducing the number of these cells in patients with COVID-19 can lead to loss of regulatory functions and consequent cytokine storm.
T276 23358-23742 Sentence denotes It has been described in several studies that COVID-19 patients have a reduced number of circulating Treg cells, which may be due to the increase in soluble IL-2 receptors (IL-2R or CD25) that potentially scavenges IL-2, reducing their bioavailability for binding to CD25 on the cell surface, thus preventing the induction of the clonal expansion signal of Treg cells (153, 192, 193).
T277 23744-23759 Sentence denotes Cytotoxic Cells
T278 23760-23858 Sentence denotes T lymphocytes CD8+ and NK are essential to control viral infections due to their cytotoxic effect.
T279 23859-24058 Sentence denotes These cells become activated after recognizing antigens attached to molecules of MHC-I presented by infected cells, which usually leads to the death of the infected cell by effector mechanisms (163).
T280 24059-24245 Sentence denotes Kamiya et al. (194) demonstrated that SARS-CoV-2 infection in humans dramatically reduces the total CD8+ and NK cell count, especially in patients who have developed more severe disease.
T281 24246-24711 Sentence denotes The inhibition of these cells was characterized by an increase in the expression of NK inhibitory receptor CD94/NK group 2 member A (NKG2A), a type C lectin receptor of cytotoxic cells that acts as a potent suppressor when binding to minimally polymorphic MHC-I that present peptide sequences of other MHC-I molecules, inducing an inhibitory signal through two receptors with tyrosine-based inhibition motifs that suppress cytokine secretion and cytotoxic activity.
T282 24712-24933 Sentence denotes In patients who recovered from COVID-19, CD8+ and NK cell counts and the reduction in NKG2A expression were restored, suggesting that the inhibition of these cells is a result of SARS-CoV-2-mediated immunomodulation (10).
T283 24934-25117 Sentence denotes Corroborating these data, it has been reported that other viral infections also manage to increase the expression of NKG2A in NK cells as a way to escape from the immune system (195).
T284 25118-25472 Sentence denotes SARS-CoV-2 studies involving CD8+ T cells have shown exhaustion of the effector capacity of these cells over time by the reduction of granzyme B, perforins, and lysosome-associated membrane protein 1, also known as LAMP-1 or CD107a, described as a marker of cytotoxic cells’ degranulation and an important parameter to assess the activity of these cells.
T285 25473-25636 Sentence denotes CD8+ T cells from COVID-19 patients have a very marked activation phenotype with an increase in CD69, CD38, CD137, and CD44, especially in critically ill patients.
T286 25637-25860 Sentence denotes However, despite presenting an increase in these activation molecules, these cells also have enhanced cell exhaustion proteins, such as PD1, Tim3, CTLA-4, and TIGIT, especially in more critically ill patients (9, 154, 170).
T287 25861-26097 Sentence denotes TIGIT receptor, present in T and NK cells, can bind to dendritic cell CD155 receptors and induce an increased expression of IL-10 and reduce IL-12, in addition to inhibiting T cell activation and blocking cytotoxicity of NK cells (196).
T288 26098-26239 Sentence denotes The use of specific blockers for these receptors, such as anti-PD1 and anti-TIGIT, has helped in the recovery of the function of these cells.
T289 26240-26441 Sentence denotes Therefore, it is logical to assume that specific NKG2A blockers could be an important tool to assist in the treatment of SARS-CoV-2 infections, restoring the functionality of cytotoxic cells (10, 195).
T290 26442-26924 Sentence denotes Together, these data described the increase in activation markers and cellular exhaustion, in addition to the reduction in functionality markers indicating that, like CD4+ T lymphocytes, these cells were probably hyperactivated right at the beginning of the infection, collaborating with the generation of a cytokine storm, until they became exhausted and lost their functional capacity, causing reduction of antigen-specific response and loss of its antiviral effects ( Figure 2 ).
T291 26925-26970 Sentence denotes Figure 2 Immune response in COVID-19 stages.
T292 26971-27029 Sentence denotes SARS-CoV-2 infection is divided into three general phases.
T293 27030-27285 Sentence denotes In the first one, called viremia, the virus spreads through the body and there is excessive activation of immune cells with exacerbated production of inflammatory mediators, such as IFN-γ, IL-2, and TNF-α, triggering cytokine storms and immune impairment.
T294 27286-27590 Sentence denotes The second (acute) phase, characterized by the appearance of COVID-19 symptoms, presents a profile of immune cells still hyperactivated, but with the presence of cell exhaustion markers, such as Tim3, PD1, TIGIT, and NKG2A, in addition to losing the functional capacity of producign IFN, IL-2, and TNF-α.
T295 27591-27863 Sentence denotes In this period there is still the appearance of CD14+ CD16+ hyperinflammatory monocytes, with a high production capacity of TNF-α, IL-1β, and IL-6, which will migrate to the lungs, contributing to the pathogenesis of respiratory failure and maintaining the cytokine storm.
T296 27864-28006 Sentence denotes The lethargic state of the immune system in the early stages of infection may be related to the delay in the generation of a humoral response.
T297 28007-28137 Sentence denotes In the third, or convalescence, phase, the individual can evolve in two opposite directions, recovery or clinical worsening/death.
T298 28138-28265 Sentence denotes In recovery, cells of lymphoid origin recover their effector function and lose markers of exhaustion, while IgG levels improve.
T299 28266-28361 Sentence denotes On the other hand, in patients with clinical worsening, this status of immune anergy continues.
T300 28363-28379 Sentence denotes Humoral Response
T301 28380-28516 Sentence denotes Detecting a humoral response against SARS-CoV-2 has been the focus of attention to developing faster and more accurate diagnostic tools.
T302 28517-28787 Sentence denotes A study assessing the presence of IgA, IgM, and IgG against SARS-CoV-2 in infected patients found that IgA levels begin to rise in the first seven days after the onset of symptoms and continue increasing until it stabilizes near the 14th day after the onset of symptoms.
T303 28788-29016 Sentence denotes Additionally, IgM production appears as early as IgA, the antibody titration in the first seven days after the onset of symptoms was very low, starting to increase only from the eighth day, reaching a plateau after the 14th day.
T304 29017-29180 Sentence denotes The average time of appearance of specific IgG against SARS-CoV-2 starts 14 days after the appearance of symptoms and grows exponentially until the 21st day (197).
T305 29181-29345 Sentence denotes These data corroborate the disease stages proposed by Lin et al. (6) (presented in the introduction), and the changes in the immune response present in the disease.
T306 29346-29522 Sentence denotes The early appearance of IgA results from the first contact of the virus with the individual’s mucosa at the moment of contagion and continues to increase until the acute phase.
T307 29523-30095 Sentence denotes Despite viremia and symptom onset, IgM levels only begin to rise from the eighth day after symptom onset, indicating anergy in the immune response during this period, perhaps caused by dysfunction in antigen-presenting cells, such as dendritic cells, and also by reducing the amount of activated T helper cells, which play a central role in triggering the immunity acquired by the activation and clonal expansion of B lymphocytes, in addition to the formation of germinal centers and generation of plasma cells that produce high affinity and avidity antibodies (198, 199).
T308 30096-30294 Sentence denotes The appearance of IgG near the third stage of the disease may be related to the clinical evolution of patients and those who fail to establish an efficient immune response might be at risk of death.
T309 30295-30439 Sentence denotes Interestingly, Guo et al. (197) found that approximately 22% of COVID-19 patients confirmed by RTq-PCR did not present detectable levels of IgM.
T310 30440-30639 Sentence denotes Most of these individuals were tested in the first seven days after the onset of symptoms, therefore the lack of IgM can be justified by the delay in generating a humoral response against SARS-CoV-2.
T311 30640-30774 Sentence denotes However, some critically ill patients followed for a longer period remained negative for IgM even 22 days after the onset of symptoms.
T312 30775-31017 Sentence denotes As for IgG levels, some patients took 30 to 40 days after the appearance of symptoms to show some detectable level of IgG, suggesting a possible failure in the production of antibodies that may have contributed to the severity of the disease.
T313 31018-31290 Sentence denotes It is possible that the generation of antibodies in more advanced stages of COVID-19 does not benefit the recovery process since most pathological mechanisms at this stage might be more related to the excess of inflammatory mediators than the presence of the virus itself.
T314 31291-31613 Sentence denotes In recovered patients, the magnitude of the production of neutralizing antibodies (nAb) against SARS-CoV-2 is positively correlated with the severity of the disease; while asymptomatic individuals have little or no capacity to produce nAb, individuals who recovered from severe cases of COVID-19 had robust nAb production.
T315 31614-31818 Sentence denotes Also, these severe recovered patients showed an increase in B cell receptor (BCR) rearrangement, which may demonstrate that the effective production of nAb requires enhanced and prolonged BCR stimulation.
T316 31819-32023 Sentence denotes Asymptomatic or mild symptomatic patients may possibly mount robust SARS-CoV-2 specific CD8 + T cell responses, which can provide protection by directly eliminating the target cells infected by the virus.
T317 32024-32148 Sentence denotes However, due to the lack of immunity provided by nAb, these individuals might suffer from SARS-CoV-2 reinfection (200, 201).
T318 32149-32562 Sentence denotes In the same way, Zhang et al. (202) also demonstrated that patients who recovered from severe COVID-19 have high levels of BCR clonal expansion and B cell activation, indicating a more robust humoral response than patients with mild disease, thus asymptomatic individuals or those with mild COVID-19 probably have different cell and humoral responses than individuals who developed the severe form of the disease.
T319 32563-32733 Sentence denotes In an article published by Chen et al, the serum of 26 patients who recovered from COVID-19 were analyzed for the production of IgG anti-SARS-CoV-2 S1 protein antibodies.
T320 32734-32946 Sentence denotes It was found that, despite the majority of patients presenting high IgG titers, only three individuals had antibodies that effectively neutralized the binding of the viral glycoprotein to the human ACE2 receptor.
T321 32947-33201 Sentence denotes In addition, the authors successfully managed to clone two different neutralizing antibodies from these patients with the ability to inhibit virus-cell binding, opening up the potential for using them as a possible source of treatment for COVID-19 (203).
T322 33202-33340 Sentence denotes In theory, the production of specific neutralizing antibodies against SARS-CoV-2 should be able to combat the virus and reduce viral load.
T323 33341-33497 Sentence denotes The production of immune memory verified in the blood of recovered patients has also been used to treat COVID-19 patients, as we will discuss further (204).