LitCovid-sentences  

PMC:7736111 / 26391-54247 JSONTXT 3 Projects

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Id Subject Object Predicate Lexical cue
T152 0-33 Sentence denotes Functional Innate Immune Response
T153 34-299 Sentence denotes A balance between successful evasion of the virus from host cell sensing pathways and the counter mechanisms developed by the host cells to overcome these inhibitory effects determines whether an early immune response could be generated or not (Liang et al., 2020).
T154 300-504 Sentence denotes Though most of the studies point towards the successful evasion mechanisms employed by CoVs, emerging evidence suggests that an adequate early antiviral response could be mounted (Park and Iwasaki, 2020).
T155 505-710 Sentence denotes That early response may hold the key for limiting the viral propagation in the majority of the COVID-19 patients (approx 80%) who are asymptomatic or develop mild symptoms and successfully clear the virus.
T156 711-845 Sentence denotes Considered the recent work on COVID-19, here we provide a detailed molecular and clinical understanding of the innate immune response.
T157 846-978 Sentence denotes We specifically discuss how these immune responses dictate the recovery from disease or development of the immunopathological state.
T158 980-999 Sentence denotes Interferon Response
T159 1000-1171 Sentence denotes By initiating an early antiviral response, signaling via IFNs and ISGs is critical for the viral clearance and an impediment for the development of the pathological state.
T160 1172-1292 Sentence denotes Several in vitro and animal studies have established the central role of these signaling pathways in SARS-CoV infection.
T161 1293-1525 Sentence denotes STAT1 knockout mice infected with SARS-CoV exhibited severe disease symptoms, conferred by increased viral replication and propagation and was further associated with reduced survival rate (Hogan et al., 2004; Frieman et al., 2010).
T162 1526-1731 Sentence denotes Similarly, SARS-CoV propagation increases in IFNR1-/- and ILFNLR1/- double knockout mice, suggesting an essential role of these signaling pathways in mitigating antiviral response (Mahlakõiv et al., 2012).
T163 1732-1844 Sentence denotes Recent in vitro studies point to a more robust IFN response generated by SARS-CoV-2 compared to its predecessor.
T164 1845-1951 Sentence denotes Epithelial cells infected with SARS-CoV-2 displayed better IFN response than cells infected with SARS-CoV.
T165 1952-2077 Sentence denotes This IFN response was STAT1 phosphorylation-dependent with subsequent expression of antiviral ISGs (Lokugamage et al., 2020).
T166 2078-2343 Sentence denotes In line with these in vitro findings, transcriptome data from bronchial alveolar lavage fluid (BALF) taken from 8 COVID-19 patients revealed extensive upregulation of about 83 ISGs, suggesting robust IFN response generated against SARS-CoV-2 (Zhou Z. et al., 2020).
T167 2344-2564 Sentence denotes Further, a study by Ziegler et al. (2020) suggested that ACE2 may also act as a type of ISG in some respiratory epithelial cells; this may point towards using ACE2 modulators as viable therapeutic options for SARS-CoV-2.
T168 2565-2704 Sentence denotes Based on the recent clinical data on COVID-19 patients, we can infer that mild/moderate patients should possess optimal early IFN response.
T169 2705-2843 Sentence denotes Whereas, weak or delayed IFN response may be the tipping point in eliciting hyperinflammatory state, allowing extensive viral propagation.
T170 2844-3036 Sentence denotes Previous studies in animal models have shown that early IFN response was the determining factor in inhibiting viral propagation and attenuating disease condition (Channappanavar et al., 2016).
T171 3037-3186 Sentence denotes In line with this, a recent study has shown that COVID-19 patients with mild/moderate conditions possess functional type I and type III IFN response.
T172 3187-3304 Sentence denotes Specifically, patients with mild/moderate symptoms have adequate levels of IFNA transcript and protein in the plasma.
T173 3305-3524 Sentence denotes The presence of detectable IFN levels in these subsets of patients was also associated with the expression of downstream signaling receptors and molecules like IFNAR1, JAK1, and TYK2, suggesting functional IFN response.
T174 3525-3652 Sentence denotes However, no IFNB mRNA or protein was detected, while optimal levels of IFN-λ were detected both at the mRNA and protein levels.
T175 3653-3797 Sentence denotes Expectedly, the levels of type I and type III IFNs positively correlated with the viral load and severity of the disease (Hadjadj et al., 2020).
T176 3798-4045 Sentence denotes In agreement with the critical role of early IFN response in attenuating infectious state, another study finds that cells pre-treated with IFN-β or IFN-λ exhibit resistance to SARS-CoV-2 infection by significantly decreasing the virus copy number.
T177 4046-4148 Sentence denotes Similarly, 3D culture organoids pre-treated with either IFN-β or IFN-λ led to reduced viral infection.
T178 4149-4363 Sentence denotes Cells depleted for either IFNAR1 or IFNLR1 had an overall increase in the number of SARS-CoV-2 infected cells, suggesting the integral role of IFN signaling in attenuating viral propagation (Stanifer et al., 2020).
T179 4364-4532 Sentence denotes Further, IFN response was adequate in younger patients compared to older ones, which may partly explain the higher risk of infection in older people (Wei et al., 2020).
T180 4533-4806 Sentence denotes Additionally, people with comorbid conditions like diabetes – a condition associated with impaired IFN response, are more susceptible to SARS-CoV-2 infection, which further points toward the critical role of IFN signaling in the early clearance of the virus (Erener, 2020).
T181 4807-5018 Sentence denotes However, a comprehensive and longitudinal analysis of the IFN response in mild/moderate patients is warranted to understand the functional consequence of this immune response throughout the disease and recovery.
T182 5019-5316 Sentence denotes Overall, considering the relatively better IFN response and ISG expression induced by SARS-CoV-2, one can argue that this functional immune response is a probable reason for the relatively lower mortality rate seen in COVID-19, compared to previous SARS-CoV and MERS infections (Meo et al., 2020).
T183 5317-5369 Sentence denotes However, these early findings warrant further proof.
T184 5371-5428 Sentence denotes Early Immune Response by Alveolar Epithelial Cells (ATII)
T185 5429-5679 Sentence denotes Activated alveolar macrophages (AM) and recruited inflammatory monocytes/macrophages are majorly responsible for the secretion of cytokines and chemokines in early phases of infection, with a substantial contribution from infected ATII cells as well.
T186 5680-5851 Sentence denotes This early response is necessary to recruit and activate the adaptive immune system and hence drive the clearance of the virus without inflicting immunopathological state.
T187 5852-6059 Sentence denotes While the levels of cytokines and chemokines are well-regulated during this phase of infection, a check on the activation profile and recruitment of these innate immune to the sites of infection is critical.
T188 6060-6415 Sentence denotes Thus, a regulated and controlled release of cytokines and chemokines in the early phase of infection is not necessarily proinflammatory but drives the successful viral clearance and the probable reason behind the limited propagation of infection as seen in the majority of the COVID-19 cases exhibiting mild symptoms (Song et al., 2020; Tay et al., 2020).
T189 6416-6658 Sentence denotes Among the cytokines secreted by virus-infected airway epithelial cells, IL-6 plays a prominent role in the early recruitment and differentiation of monocytes, neutrophils, and lymphocytes which express the corresponding IL-6 receptor (IL-6R).
T190 6659-6811 Sentence denotes Though IL-6 is chiefly secreted by macrophages (activated AMs and inflammatory macrophages) in the lungs, secretion of IL-6 by ATII is also significant.
T191 6812-6994 Sentence denotes In vitro studies on SARS-CoV have shown the release of IL-6 by ATII in response to RIG-I and TLR signaling via activation of NF κB pathway (Ndlovu et al., 2009; Tanaka et al., 2012).
T192 6995-7174 Sentence denotes Additionally, proinflammatory cytokines TNF-α and IL-1β secreted by macrophages act on ATII cells to cause the release of IL-6 (Crestani et al., 1994; Schwingshackl et al., 2013).
T193 7175-7444 Sentence denotes Transcriptional profiling in normal human bronchial epithelial (NHBE) infected with SARS-CoV-2 shows upregulation of IL-6, suggesting that these lung epithelial cells may contribute to early IL-6 response seen in non-severe COVID-19 patients (Blanco-Melo et al., 2020).
T194 7445-7630 Sentence denotes However, more conclusive studies like tissue immunohistochemistry or single-cell immuno-profiling of the lung epithelial cells will clarify their contribution in IL-6 secretion in vivo.
T195 7632-7677 Sentence denotes Early Immune Response by Alveolar Macrophages
T196 7678-7837 Sentence denotes Lung resident macrophages like AM are generally present in the terminal airways where they serve a regulatory function to maintain normal cellular homeostasis.
T197 7838-7952 Sentence denotes Previous studies have defined a critical role of these cells in successful viral clearance (Hartwig et al., 2014).
T198 7953-8093 Sentence denotes Depletion of these cells in animals infected with mouse hepatitis virus type 1 (MHV-1) resulted in a marked reduction of antiviral response.
T199 8094-8159 Sentence denotes AMs have also been shown indispensable during SARS-CoV infection.
T200 8160-8284 Sentence denotes The depletion of these cells was associated with worsened disease outcomes in a mouse model of SARS-CoV (Page et al., 2012).
T201 8285-8485 Sentence denotes Further, BALF fluid analysis of SARS-CoV infected patients revealed an increase in AM population, which persisted over two months and significantly correlated with viral clearance (Wang et al., 2005).
T202 8486-8768 Sentence denotes In addition to their activation by the secondary response during viral infection, few in vitro studies have shown that these cells can also be directly targeted by SARS-CoV (Mossel et al., 2008; Joel Funk et al., 2012), though contradictory reports are available (Yip et al., 2014).
T203 8769-8991 Sentence denotes Overall, the data supporting the antiviral response by AMs cells is largely based on other respiratory infections like influenza virus and MERS, with a few reports on SARS-CoV (Mossel et al., 2008; Joel Funk et al., 2012).
T204 8992-9236 Sentence denotes Studying these responses in COVID-19 patients may be challenging due to technical limitations (like difficulty in obtaining the optimal number of these cells from the lungs and their rapid functional and phenotypic changes during cell culture).
T205 9237-9372 Sentence denotes However, we can draw inferences from other cell types and correlate specific markers from cells directly obtained from the lung tissue.
T206 9373-9523 Sentence denotes One such recent elegant study using scRNA-seq and cluster analysis revealed the activation status of AMs in BALF fluid derived from COVID-19 patients.
T207 9524-9684 Sentence denotes The analysis is based on the signature genes expressed by these cells, which are markedly different from recruited inflammatory macrophages (Liao et al., 2020).
T208 9685-9865 Sentence denotes Surprisingly, the number of these cells declined in patients with severe disease symptoms, and the presence of proinflammatory macrophages can take their place (Liao et al., 2020).
T209 9866-10038 Sentence denotes A recent study (pre-print, not yet peer-reviewed) has shown infection and propagation of SARS-CoV-2 in macrophages present in lymph nodes and spleen (Chen Y. et al., 2020).
T210 10039-10159 Sentence denotes However, direct infection and replication of the virus was not explored in detail, specifically under in vitro settings.
T211 10160-10279 Sentence denotes Previous studies on SARS-CoV suggest low replication in these cells, probably due to phagocytosis (Yilla et al., 2005).
T212 10280-10634 Sentence denotes Thus, these results suggest that AMs’ response to SARS-CoV-2 may be complicated but necessary for the activation and recruitment of other innate cells like monocytes, dendritic cells, neutrophils, natural killer (NK) cells, and essential in the regulation of the adaptive immune system (Soroosh et al., 2013; Hartwig et al., 2014; Meischel et al., 2020).
T213 10636-10672 Sentence denotes Dysfunctional Innate Immune Response
T214 10673-10893 Sentence denotes On average, about 15% of the COVID-19 patients exhibit severe disease symptoms whereas 5% become critical, but the figures are subject to change owing to the ongoing increase in the number of cases (Berlin et al., 2020).
T215 10894-11228 Sentence denotes By looking at the immunological trajectories of these patients, it has become evident that impaired early IFN response followed by hyperactivated innate and a dysfunctional adaptive immune response is the vital pathological factors contributing to disease severity in COVID-19 patients (Blanco-Melo et al., 2020; Mathew et al., 2020).
T216 11229-11459 Sentence denotes However, there are also reports, suggesting a more complex interplay in these immune responses, which needs a thorough understanding of developing effective immunotherapy-based interventions and for successful vaccine development.
T217 11461-11489 Sentence denotes Impaired Interferon Response
T218 11490-12174 Sentence denotes Based on previous molecular and clinical studies on SARS-CoV and the recent data on SARS-CoV-2, it is becoming evident that the delay in primary IFN response may be due to multiple factors such as (1) poor overall immune function of a patient with a compromised adaptive response as in older people, (2) patients with comorbidity, (3) genetic factors or epigenetic changes associated with crucial genes and transcriptional factors involved in IFN signaling, and (4) age and sex of the patient, probably making the older individuals and males more susceptible to COVID-19 (Bastard et al., 2020; Li M.Y. et al., 2020; Nguyen et al., 2020; Verdecchia et al., 2020; Zhou F. et al., 2020).
T219 12175-12285 Sentence denotes Thus, overall these factors may compromise the host cell immune system and delay the early antiviral response.
T220 12286-12440 Sentence denotes Especially in the case of RNA viruses, evasion of host immune response is managed by interfering with PRRs, PLRs, TLRs, and IFN signaling (Kikkert, 2020).
T221 12441-12593 Sentence denotes Additionally, inhibition is also conferred by hijacking host cell biosynthetic machinery and eventually inducing host cell apoptosis as discussed above.
T222 12594-12794 Sentence denotes Previous studies have unequivocally demonstrated poor IFN response to SARS-CoV during severe infection, which is also apparently the case with SARS-CoV-2, reviewed recently by Park and Iwasaki (2020).
T223 12795-12940 Sentence denotes In vitro culture of the primary lung, epithelial cells infected with the SARS-CoV-2 generated inadequate IFN response (Blanco-Melo et al., 2020).
T224 12941-13077 Sentence denotes By looking at the clinical samples, a large body of data suggests impaired IFN signaling in severe and critically ill COVID-19 patients.
T225 13078-13309 Sentence denotes Blood analysis from across the studies reveals low or undetectable levels of IFN-β and IFN-λ levels in patients exhibiting severe disease symptoms or patients admitted to the ICU with in a critical condition (Hadjadj et al., 2020).
T226 13310-13449 Sentence denotes Of note, an elegant study was conducted to explore the functional role of IFN signaling during various stages of COVID-19 disease severity.
T227 13450-13594 Sentence denotes The study found robust impairment of IFN signaling in critically ill and severe patients in comparison to mild/moderate and healthy individuals.
T228 13595-13787 Sentence denotes IFN-β mRNA and protein were undetectable in all patients, whereas IFN-α2 protein was highly reduced in the plasma of severe and critically ill patients, corroborated with reduced IFN activity.
T229 13788-14002 Sentence denotes In line with the impaired IFN signaling, robust downregulation of some of the ISGs (MX1, IFITM1, IFIT2) observed in severe and critically ill patients suggest an overall reduced IFN response (Hadjadj et al., 2020).
T230 14003-14196 Sentence denotes Consistent with the low circulating levels of IFNs, transcriptional analysis of post-mortem lung samples further confirmed these observations and revealed no detectable type I or Type III IFNs.
T231 14197-14354 Sentence denotes Among the SARS-CoV-2 proteins which directly interfere with IFN response, ORF6, ORF8, and N protein inhibit IFN-β and NF-κB signaling (Li J.Y. et al., 2020).
T232 14355-14481 Sentence denotes Further, Konno et al. (2020) have identified a more extended variant of ORF3b with presumably more vigorous anti-IFN activity.
T233 14482-14598 Sentence denotes Thus, these early observations may point towards an impaired early IFN response by the host cells against SARS-CoV-2
T234 14599-14759 Sentence denotes Adding to the essential role of IFN in early antiviral response, two recent studies have shown that genetic changes are associated with inadequate IFN response.
T235 14760-14914 Sentence denotes In the first study, the presence of IFN neutralizing auto-antibodies found in patients who exhibited more severe disease condition (Bastard et al., 2020).
T236 14915-15035 Sentence denotes These auto-antibodies were more prevalent in men than women, that partly explains the susceptibility of men to COVID-19.
T237 15036-15106 Sentence denotes None of the asymptomatic or mild cases had detectable auto-antibodies.
T238 15107-15241 Sentence denotes In the other study, mutations in 13 key genes implicated in TLR3- and IRF7-dependent exhibit loss-of-function (Zhang Q. et al., 2020).
T239 15242-15396 Sentence denotes Patients or the cells derived from these patients with loss-of-function in these genes had inadequate IFN response and vulnerable to SARS-CoV-2 infection.
T240 15397-15572 Sentence denotes In a similar study on four patients with severe disease symptoms, the whole exome-sequencing revealed loss-of-function of TLR7, which is essentially involved in IFN signaling.
T241 15573-15713 Sentence denotes These patients exhibited decreased expression of IRF7, IFNB1, and ISG15, along with reduced production of IFN-γ (Van Der Made et al., 2020).
T242 15714-16040 Sentence denotes Thus, impaired IFN signaling, mediated either directly by the virus by interfering at various steps in the IFN signaling, or genetic predisposition of some individuals to inadequate IFN response and presence of IFN neutralizing auto-antibodies are some of the significant factors which determine the COVID-19 disease severity.
T243 16041-16245 Sentence denotes The dysfunctional IFN response in conjunction with other innate and adaptive immune responses may thus decide the path to recovery or progression to more severe form of the disease (Hadjadj et al., 2020).
T244 16246-16396 Sentence denotes Impaired type I interferon activity and exacerbated inflammatory responses in severe COVID-19 patients (Hadjadj et al., 2020; Park and Iwasaki, 2020).
T245 16397-16572 Sentence denotes A comprehensive understanding of the molecular mechanisms by which SARS-CoV-2 causes impaired IFN response is still lacking, and future studies may help us to understand this.
T246 16573-16751 Sentence denotes Nevertheless, these initial reports, along with the previous findings on SARS-CoV, are the basis behind exploring the therapeutic efficacy of IFN treatment for COVID-19 patients.
T247 16752-16901 Sentence denotes Currently, there are ongoing clinical trials with IFN-β1a (NCT04350671), which is in phase II, and IFN-l (NCT04388709) for the treatment of COVID-19.
T248 16902-17007 Sentence denotes The preliminary results with these drugs have been encouraging as of now (Davoudi-Monfared et al., 2020).
T249 17009-17086 Sentence denotes Release of Damage-Associated Molecular Patterns and Proinflammatory Molecules
T250 17087-17255 Sentence denotes The impaired early IFN response results in high viral propagation that subsequently leads to the induction of a robust proinflammatory response (Davidson et al., 2015).
T251 17256-17491 Sentence denotes The cytopathic nature of these viruses induces substantial death in infected ATII cells (apoptotic as well as necrotic) which leads to the release of a wide range of damage-associated molecular patterns (DAMPs) and cytotoxic molecules.
T252 17492-17624 Sentence denotes Similarly, activated AMs also respond to the released DAMPs and act concurrently with PAMPs to amplify the proinflammatory response.
T253 17625-17752 Sentence denotes A list and role of potential PAMPs, DAMPs, and their respective PRRs have been reviewed previously (Leiva-Juárez et al., 2018).
T254 17753-17858 Sentence denotes Circulating nuclear and mitochondrial DNA, and histones serve as potential DAMPs during viral infections.
T255 17859-17960 Sentence denotes These molecules signal via the TLR pathway and induce robust expression of proinflammatory molecules.
T256 17961-18161 Sentence denotes Among the DAMPs secreted by virus-infected and damaged epithelial cells, the role of high-mobility group box one protein (HMGB1) and S100 are well known (Leiva-Juárez et al., 2018; Gong et al., 2020).
T257 18162-18269 Sentence denotes HMGB1 after binding to TLR4 induces activation of NF-κB signaling and release of proinflammatory molecules.
T258 18270-18454 Sentence denotes Additionally, HMGB1 also activates receptors like TREM1/2, and receptors for advanced glycation end products (RAGE) which are also involved in NF-κB activation (Yang and Tracey, 2010).
T259 18455-18620 Sentence denotes S100 initiates similar downstream signaling after binding with TLR4 and RAGE receptors (Ma et al., 2017), these studies were recently reviewed by Gong et al. (2020).
T260 18621-18798 Sentence denotes Previous animal studies with other respiratory viruses have shown a close correlation of increased serum HMGB1 levels with lung injury and disease severity (Patel et al., 2018).
T261 18799-18961 Sentence denotes Similarly, elevated expression of S100A9 was present in patients during acute lung injury mediated by the respiratory syncytial viral (RSV; Foronjy et al., 2016).
T262 18962-19254 Sentence denotes Although as of now, presence of HMGB1 has no report in COVID-19 patients, the damage in the lung parenchyma in post-mortem biopsies suggests that it is highly likely that this protein may implicate in disease pathogenesis and hyperinflammation (Andersson et al., 2020; Zhang Q. et al., 2020).
T263 19255-19464 Sentence denotes Increased expressions of S100A8, S100A9, and S100A12 calgranulins found in the BALF fluid from COVID-19 patients indicate their potential role in generating the proinflammatory response (Zhou Z. et al., 2020).
T264 19465-19614 Sentence denotes Further, Zou et al. (2020) showed increased presence of cell-free DNA and citrullinated histones in blood samples obtained from 50 COVID-19 patients.
T265 19615-19773 Sentence denotes Studies on other inflammatory diseases have shown a close correlation between the presence of these molecules with disease severity (Resman Rus et al., 2016).
T266 19774-19958 Sentence denotes However, their functional role is yet unexplored, but the increased expression of some of these DAMPs in COVID-19 patients suggests their potential implication in disease pathogenesis.
T267 19959-20104 Sentence denotes Future studies will clarify the involvement of various other DAMPs in perpetuating the proinflammatory state, and specifically the role of HMGB1.
T268 20105-20269 Sentence denotes In addition to the secretion of DAMPs, AM and virus infected ATII cells secrete a range of pro-inflammatory molecules (Hussell and Bell, 2014; Glaser et al., 2019).
T269 20270-20468 Sentence denotes Among these, increased IL-6 levels are consistently detected in cultured cells infected with SARS-CoV and SARS-CoV-2 (Ye et al., 2018; Herold et al., 2020; Liu J. et al., 2020; Liu T. et al., 2020).
T270 20469-20727 Sentence denotes Notably, levels of TNF-α, IL-8, IL-10, GM-CSF, CXCL10, and CCL5 secreted by infected ATII and activated AMs were also consistently shown to increase during SARS-CoV and SARS-CoV-2 infections (Ward et al., 2005; Huang C. et al., 2020; Patterson et al., 2020).
T271 20728-21050 Sentence denotes Transcriptional profiling of cytokines and chemokines in normal human lung epithelial cells (NHBE) infected with SARS-CoV-2 revealed increased levels of CCL20, CXCL1, IL-1B, IL-6, CXCL3, CXCL5, CXCL6, CXCL2, CXCL16, and TNF-α by primary lung epithelial cells in response to SARS-CoV-2 infection (Blanco-Melo et al., 2020).
T272 21051-21202 Sentence denotes Thus, lung resident ATII and AM cells besides being integral to the antiviral response also participate in generating a profound proinflammatory state.
T273 21204-21268 Sentence denotes Proinflammatory Molecules Released by Infiltrating Myeloid Cells
T274 21270-21316 Sentence denotes Circulating inflammatory monocytes/macrophages
T275 21317-21440 Sentence denotes A detailed account of the role of inflammatory macrophages in the pathogenesis of SARS-CoV is reported by He et al. (2007).
T276 21441-21670 Sentence denotes Animal studies have demonstrated extensive recruitment and accumulation of these cells in the lungs, which correlated with the release of TNF-α, IL-1β, and IL-6 and the development of ARDS, reviewed by Gralinski and Baric (2015).
T277 21671-21896 Sentence denotes Interestingly, depletion of these inflammatory macrophages in animals infected with SARS-CoV was associated with a high recovery rate, thus suggesting their critical role in disease pathogenesis (Channappanavar et al., 2016).
T278 21897-22078 Sentence denotes Similarly, SARS-CoV infection in animals with STAT1 knockout in alternatively activated macrophages displayed attenuated lung damage and protection from disease (Page et al., 2012).
T279 22079-22247 Sentence denotes Besides, a large number of clinical studies support an integral role of IMMs in SARS-CoV infected patients (Wong et al., 2004; Tisoncik et al., 2012; Liu et al., 2019).
T280 22248-22453 Sentence denotes Recent studies from BALF from COVID-19 patients have also demonstrated the critical role of circulating monocyte-derived macrophages in the induction of robust proinflammatory reaction (Liao et al., 2020).
T281 22454-22579 Sentence denotes Blood cell analysis of 18 COVID-19 patients revealed an activated status of inflammatory macrophages (Zhang D. et al., 2020).
T282 22580-22736 Sentence denotes In line with these findings, scRNA-seq followed by immune cell profiling of blood cells revealed an increased number of CD14++ monocytes (Wen et al., 2020).
T283 22737-22874 Sentence denotes Severe and critically ill patients also exhibit macrophage activation syndrome (MAS) in some cases (Giamarellos-Bourboulis et al., 2020).
T284 22875-23029 Sentence denotes Thus, all the evidence directs towards a critical role of inflammatory macrophages in disease severity during COVID-19 and a potential therapeutic target.
T285 23030-23206 Sentence denotes Intervention which reduces the impetus to induce MAS like antibodies directed against IL-6 and IL-1β has shown promising clinical outcomes, reviewed by Otsuka and Seino (2020).
T286 23208-23235 Sentence denotes Proinflammatory neutrophils
T287 23236-23465 Sentence denotes Like other innate immune cells, neutrophils are protective in the early phases of infection by neutralizing the viral particles and release of protective molecules to interfere with the viral propagation (Drescher and Bai, 2013).
T288 23466-23603 Sentence denotes However, in severe cases, the number of these cells increases at the sites of infection and they become the leading damage-causing cells.
T289 23604-23854 Sentence denotes Excessive infiltration of these cells in the lungs is associated with secretion of TNF-α, IL-6, IL-1β, IL-7, IL-23, and IL-36, along with a broad range of other cytokines and damage-causing neutrophil extracellular traps (NETs; Tecchio et al., 2014).
T290 23855-24034 Sentence denotes Additionally, these neutrophils also secrete a range of chemokines like CCL2/3/4, CXCL1-13 to attract more neutrophils and monocytes from the circulation (Sokol and Luster, 2015).
T291 24035-24124 Sentence denotes Emerging evidence suggests a pivotal role of neutrophils in the pathogenesis of COVID-19.
T292 24125-24339 Sentence denotes Immune cell profiling revealed activated status of these cells which was associated with increased levels of NETs and correlated with acute-phase reaction (Chen G. et al., 2020; Qin et al., 2020; Zuo et al., 2020).
T293 24340-24487 Sentence denotes Similarly, an increase in the number of activated neutrophils was present in the BALF of COVID-19 patients (Liao et al., 2020; Xiong et al., 2020).
T294 24488-24650 Sentence denotes Thus, based on these recently published studies, the neutrophil number in the blood can be used as a predictive marker for disease severity (Zhang et al., 2020a).
T295 24652-24672 Sentence denotes Natural killer cells
T296 24673-24875 Sentence denotes Natural killer cells are essential in the early phase of viral infection to assist in the clearance of the virus by interacting with death receptors expressed on the infected cells (Vidal et al., 2011).
T297 24876-25023 Sentence denotes Previous clinical studies have shown decreased NK cell number in SARS-CoV patients, which was more pronounced in severe cases (Wang and Xia, 2004).
T298 25024-25266 Sentence denotes A recent blood profile of COVID-19 patients suggested a similar decline in the number of NK cells in severe cases, along with an increased expression of exhaustion markers (Chen X. et al., 2020; Tan L. et al., 2020b; Zheng H.Y. et al., 2020).
T299 25267-25413 Sentence denotes On the contrary, no significant difference was found in the number of total NK cells, in non-ICU vs 10 ICU admitted patients (Zhou et al., 2020a).
T300 25414-25570 Sentence denotes This discrepancy in number could probably be due to differential temporal immune response and the underlying prevailing disease conditions in some patients.
T301 25571-25799 Sentence denotes Immune cell profiling data from early recovery stage (ERS) and late recovery stage (LRS) COVID-19 patients revealed a biphasic effect, with fewer NK cells during early recovery ERS, which recovered during LRS (Wen et al., 2020).
T302 25800-25972 Sentence denotes Thus, besides the underlying disease state, the NK cell number may also be sensitive to the time of sample collection and hence may not serve as a potential disease marker.
T303 25973-26263 Sentence denotes Further, these studies could also suffer from the limitation of the variation in the age of the patients studied which may make it difficult to provide a definite role of these cells concerning COVID-19 disease severity (Nikolich-Zugich et al., 2020), necessitating more conclusive studies.
T304 26265-26315 Sentence denotes Lung resident and monocyte-derived dendritic cells
T305 26316-26463 Sentence denotes Lung resident dendritic cells majorly have a protective role during the early onset of the disease by activating the adaptive immune cell response.
T306 26464-26738 Sentence denotes Under the influence of PAMPs, DAMPs, and inflammatory cytokine signaling, lung resident dendritic cells are conditioned and migrate to the draining lymph node under the influence of CCR7 where they prime naïve CD4+ and CD8+ T cells (Braun et al., 2011; Thaiss et al., 2011).
T307 26739-26901 Sentence denotes In contrast, monocyte-derived dendritic cells generate under the influence of GM-CSF, IFN-γ, and IL-4, along with other proinflammatory signals (Qu et al., 2014).
T308 26902-27086 Sentence denotes Previous studies have shown elevated secretions of CCL3, CCL5, MCP-1, IP-10, TNF-α, and IL-6 by activated inflammatory dendritic cells (DCs) in response to SARS-CoV (Law et al., 2005).
T309 27087-27178 Sentence denotes Recent reports also suggest the presence of activated dendritic cells in COVID-19 patients.
T310 27179-27430 Sentence denotes Notably, meta-transcriptomic sequencing of BALF obtained from 8 COVID-19 patients revealed an activated status of these cells along with neutrophils, as compared to other innate and adaptive immune cells (Yang A.P. et al., 2020; Zhou Z. et al., 2020).
T311 27431-27856 Sentence denotes Thus, based on previous clinical studies on SARS-CoV infection and recent emerging studies on SARS-CoV-2, it is evident that hyperinflammatory immune response in severe and critically ill COVID-19 patients is mainly mounted by infiltrated innate immune cells at the site of infection with a substantial contribution by the adaptive immune cells as discussed below in the section on the dysfunctional adaptive immune response.