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LitCovid-PMC-OGER-BB

LitCovid-PD-FMA-UBERON

LitCovid-PD-UBERON

{"project":"LitCovid-PD-UBERON","denotations":[{"id":"T19","span":{"begin":647,"end":660},"obj":"Body_part"},{"id":"T20","span":{"begin":758,"end":762},"obj":"Body_part"},{"id":"T21","span":{"begin":2783,"end":2788},"obj":"Body_part"},{"id":"T22","span":{"begin":2866,"end":2871},"obj":"Body_part"},{"id":"T23","span":{"begin":3977,"end":3982},"obj":"Body_part"},{"id":"T24","span":{"begin":4199,"end":4204},"obj":"Body_part"},{"id":"T25","span":{"begin":5313,"end":5318},"obj":"Body_part"},{"id":"T26","span":{"begin":6487,"end":6492},"obj":"Body_part"},{"id":"T27","span":{"begin":6594,"end":6599},"obj":"Body_part"},{"id":"T28","span":{"begin":8650,"end":8655},"obj":"Body_part"}],"attributes":[{"id":"A19","pred":"uberon_id","subj":"T19","obj":"http://purl.obolibrary.org/obo/UBERON_0002405"},{"id":"A20","pred":"uberon_id","subj":"T20","obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"A21","pred":"uberon_id","subj":"T21","obj":"http://purl.obolibrary.org/obo/UBERON_0000178"},{"id":"A22","pred":"uberon_id","subj":"T22","obj":"http://purl.obolibrary.org/obo/UBERON_0000178"},{"id":"A23","pred":"uberon_id","subj":"T23","obj":"http://purl.obolibrary.org/obo/UBERON_0000178"},{"id":"A24","pred":"uberon_id","subj":"T24","obj":"http://purl.obolibrary.org/obo/UBERON_0000178"},{"id":"A25","pred":"uberon_id","subj":"T25","obj":"http://purl.obolibrary.org/obo/UBERON_0000178"},{"id":"A26","pred":"uberon_id","subj":"T26","obj":"http://purl.obolibrary.org/obo/UBERON_0000178"},{"id":"A27","pred":"uberon_id","subj":"T27","obj":"http://purl.obolibrary.org/obo/UBERON_0000178"},{"id":"A28","pred":"uberon_id","subj":"T28","obj":"http://purl.obolibrary.org/obo/UBERON_0000178"}],"text":"NK Cell Role in Clearing Acute Coronavirus Infections\nThere is currently a paucity of studies into the role of NK cells not only in COVID-19 pathophysiology, but also in other coronavirus infections. An in vivo study reported that beige mice on a B6 background cleared SARS-CoV-1 normally, indicating that functional lymphocytes, including NK cells, may not be required to eliminate SARS-CoV-1 in murine models (119). However, in a more recent study characterizing the cellular immune response to SARS-CoV-1 in 12–14-month old BALB/c mice, T cell depletion did not prevent control of SARS-CoV-1 replication (120), suggesting a role for the innate immune system, and NK cells, in viral clearance. Importantly, in this study CD4-depletion resulted in enhanced lung immunopathology and delayed viral clearance, while CD8-depletion did not affect viral replication or clearance, thus highlighting an important role for CD4+ T cells in coronavirus infection. These conflicting results may be due to the inherent limitations of CoV murine models. In 4–8 week-old mice, SARS-CoV-1 is associated only with mild pneumonitis and cytokines are not detectable in the lungs (119, 121, 122). A SARS-CoV-1 isolate (MA-15) replicates to a high titer and is associated with viremia and mortality, however the model lacks significant inflammatory cell infiltration into the lungs (123). Thus, mouse models developed for the study of SARS fell short in terms of reproducing the clinical and histopathological signs of disease (119, 121–123). It is therefore necessary to develop a usable animal model that is capable of reproducing the clinical and histopathological signs on COVID-19. Israelow et al. recently described a SARS-CoV-2 murine model based on adeno associated virus (AAV)9-mediated expression of human (h)ACE2, which replicated the pathologic findings found in COVID-19 patients (124). This model, which overcame the inability of murine (m)ACE2 to support SARS-CoV-2 infection, was used to show the inability of Type I IFN to control SARS-CoV-2 replication (124). In a similar attempt to overcome the lack of infectability through mACE2, Dinnon et al. recently described a recombinant virus (SARS-CoV-2 MA) with a remodeled S protein mACE2 interface, which replicated in upper and lower airways in young and aged mice with disease being more severe in aged mice. The authors used this model to screen therapeutics from vaccine challenge studies and assessed pegylated IFN-λ-1 as a promising therapeutic. The authors suggested that this model has greater ease of use, cost, and utility over transgenic hACE2 models (125) to evaluate vaccine and therapeutic efficacy in mice (126).\nA preliminary analysis of NK cell function and phenotype has been performed by Zheng et al. using peripheral blood from COVID-19 patients (127). On admission, NK cell levels in the peripheral blood inversely correlated with disease severity. Furthermore, COVID-19 patients with severe disease had significantly lower numbers of circulating NK cells, as compared to mild disease (p \u003c 0.05) (127). Additionally, circulating NK cells in severe disease displayed increased expression of the inhibitory receptor NKG2A and had an hyporesponsive phenotype with lower levels of IFN-γ, tumor necrosis factor (TNF)-α, IL-2, and granzyme B, although degranulation was maintained (127). Finally, as compared to patients with active disease, patients recovering from COVID-19 had higher numbers of NK cells and lower NKG2A expression (127). Liao et al. performed single-cell RNAseq on the cells obtained from bronchoalveolar lavage fluid of severe and mild COVID-19 patients and found that COVID-19 patients had significantly more NK cell infiltrates into the lungs, however patients with severe disease had reduced proportions of NK cells (128). In addition, KLRC1 (NKG2A) and KLRD1 (CD94) were highly expressed by NK cells (128). Carvelli et al. analyzed myeloid and lymphoid populations by immunophenotyping from blood and bronchoalveolar lavage fluid (BALF) in 10 healthy controls, 10 paucisymptomatic COVID-19 patients, 34 pneumonia patients, and 28 patients with ARDS due to SARS-CoV-2 and found that absolute numbers of peripheral blood lymphocytes, including NK cells, were significantly reduced in the pneumonia and ARDS groups compared to healthy controls. Furthermore, the proportion of mature NK cells was reduced in patients with ARDS and NK cells showed increased NKG2A, PD-1, and CD39 (129). Finally, Wilk et al. performed single-cell RNA-sequencing on 7 COVID-19 patients and 6 healthy controls and found that the CD56bright population was depleted in all COVID-19 patients but the CD56dim population was depleted only in patients with severe COVID-19. Furthermore, NK cells had increased expression of the exhaustion markers LAG3 and HAVCR2 (130). NK cell cytopenia seems to be a consistent characteristic among SARS-CoV-2 infected patients (131). Altogether, these data indicate alterations in the NK cell phenotype and functional profile that are consistent with the hypothesis that to establish a productive and lasting infection, SARS-CoV-2 needs to dampen the NK cell response.\nNK cell dysfunctions were also observed in patients from the previous CoV outbreaks. Wang et al. assessed NK cell number and phenotype using peripheral blood from 221 SARS patients admitted to hospitals in Beijing, China (132). NK cell proportion and absolute number were significantly reduced in SARS patients as compared to healthy donors and patients infected with the bacterium Mycoplasma pneumoniae (131). NK cell number correlated inversely with disease severity and patients with anti-SARS CoV-specific IgG or IgM antibodies had significantly fewer NK cells (132). The patients assessed had varied disease duration from 4 to 72 days (mean 31.7 days) and this allowed for patient stratification by disease duration. Within the first 10 days of SARS-CoV-1 infection, NK cell numbers remained high but this period was followed by the development of lymphopenia with levels recovering only around day 40 (132). Dong et al. also observed a reduction of NK cell numbers in SARS patients, and these levels were lower in patients with severe, as compared to mild, SARS (133). In addition, MERS infection is strongly associated with leuko- and lymphopenia (42, 134–136).\nThe mechanisms underlying the reduction of circulating NK cells in patients infected with CoVs are still unclear. As most studies have focused on peripheral blood NK cells, it is possible that the reduced number of circulating NK cells is due to redistribution of blood NK cells into the infected tissues (137). While it is hard to assess NK cell migration to infected tissues in COVID-19 patients, this hypothesis was corroborated by mouse studies, where NK cells have been shown to migrate to the lungs in CoV infected animals (120).\nAn abundance of inhibitory factors, such as TGF-β, may be partially responsible for the NK cell hyporesponsiveness observed in COVID-19 patients. In support of this hypothesis, Huang et al. found significantly higher TGF-β levels in SARS patients compared to healthy controls and this positively correlated with length of stay (138). Given the importance of TGF-β in suppressing NK cell functions, it is possible that the higher levels of TGF-β (as well as other inhibitory cytokines) in CoV patients leads to suppression of NK cell antiviral activity (138). Early studies of COVID-19 patients report secondary (super-) infections, including nosocomial pneumonia or bacteremia as a complication of SARS-CoV-2 infection (138). Since NK cells are critical first responders that play a role in preventing and clearing infections (139), a poor NK cell count or exhausted phenotype, in addition to negatively influencing COVID-19 patient outcomes, could facilitate the development of secondary infections and have a significant negative impact on patient outcomes.\nOne of the main barriers in studying the role of NK cell activation in the early clearance of CoV infection in asymptomatic or mildly symptomatic patients is the fact that these individuals are rarely diagnosed in the clinic and therefore an opportunity to collect samples for research does not exist. Thus, while there is currently no direct evidence to support a role for NK cells in the clearance of SARS-CoV-2, evidence showing that viral infection has a negative effect on the NK cell compartment is accumulating. Given the importance of NK cell activity in early viral clearance and late immunopathology, having a rapid and reliable test to predict NK cell function, such as NKVue™ (ATGen Canada/NKMax), whereby whole blood is stimulated by an NK cell-specific activating cytokine mix and activity is measured via IFN-γ production, might allow researchers to predict who will mount an adequate response with asymptomatic or minimally symptomatic viral clearance and who will need ICU admission, as has been shown with cancer patients (140). Further research will be required into the innate immune response to CoV infection to more fully understand NK cell contributions to viral clearance."}

LitCovid-PD-MONDO

LitCovid-PD-CLO

LitCovid-PD-CHEBI

{"project":"LitCovid-PD-CHEBI","denotations":[{"id":"T41","span":{"begin":1200,"end":1202},"obj":"Chemical"},{"id":"T44","span":{"begin":2197,"end":2199},"obj":"Chemical"},{"id":"T47","span":{"begin":2220,"end":2227},"obj":"Chemical"},{"id":"T48","span":{"begin":3282,"end":3284},"obj":"Chemical"},{"id":"T50","span":{"begin":4446,"end":4448},"obj":"Chemical"},{"id":"T51","span":{"begin":7399,"end":7408},"obj":"Chemical"}],"attributes":[{"id":"A41","pred":"chebi_id","subj":"T41","obj":"http://purl.obolibrary.org/obo/CHEBI_474859"},{"id":"A42","pred":"chebi_id","subj":"T41","obj":"http://purl.obolibrary.org/obo/CHEBI_73610"},{"id":"A43","pred":"chebi_id","subj":"T41","obj":"http://purl.obolibrary.org/obo/CHEBI_90325"},{"id":"A44","pred":"chebi_id","subj":"T44","obj":"http://purl.obolibrary.org/obo/CHEBI_474859"},{"id":"A45","pred":"chebi_id","subj":"T44","obj":"http://purl.obolibrary.org/obo/CHEBI_73610"},{"id":"A46","pred":"chebi_id","subj":"T44","obj":"http://purl.obolibrary.org/obo/CHEBI_90325"},{"id":"A47","pred":"chebi_id","subj":"T47","obj":"http://purl.obolibrary.org/obo/CHEBI_36080"},{"id":"A48","pred":"chebi_id","subj":"T48","obj":"http://purl.obolibrary.org/obo/CHEBI_63895"},{"id":"A49","pred":"chebi_id","subj":"T48","obj":"http://purl.obolibrary.org/obo/CHEBI_74072"},{"id":"A50","pred":"chebi_id","subj":"T50","obj":"http://purl.obolibrary.org/obo/CHEBI_74756"},{"id":"A51","pred":"chebi_id","subj":"T51","obj":"http://purl.obolibrary.org/obo/CHEBI_22587"}],"text":"NK Cell Role in Clearing Acute Coronavirus Infections\nThere is currently a paucity of studies into the role of NK cells not only in COVID-19 pathophysiology, but also in other coronavirus infections. An in vivo study reported that beige mice on a B6 background cleared SARS-CoV-1 normally, indicating that functional lymphocytes, including NK cells, may not be required to eliminate SARS-CoV-1 in murine models (119). However, in a more recent study characterizing the cellular immune response to SARS-CoV-1 in 12–14-month old BALB/c mice, T cell depletion did not prevent control of SARS-CoV-1 replication (120), suggesting a role for the innate immune system, and NK cells, in viral clearance. Importantly, in this study CD4-depletion resulted in enhanced lung immunopathology and delayed viral clearance, while CD8-depletion did not affect viral replication or clearance, thus highlighting an important role for CD4+ T cells in coronavirus infection. These conflicting results may be due to the inherent limitations of CoV murine models. In 4–8 week-old mice, SARS-CoV-1 is associated only with mild pneumonitis and cytokines are not detectable in the lungs (119, 121, 122). A SARS-CoV-1 isolate (MA-15) replicates to a high titer and is associated with viremia and mortality, however the model lacks significant inflammatory cell infiltration into the lungs (123). Thus, mouse models developed for the study of SARS fell short in terms of reproducing the clinical and histopathological signs of disease (119, 121–123). It is therefore necessary to develop a usable animal model that is capable of reproducing the clinical and histopathological signs on COVID-19. Israelow et al. recently described a SARS-CoV-2 murine model based on adeno associated virus (AAV)9-mediated expression of human (h)ACE2, which replicated the pathologic findings found in COVID-19 patients (124). This model, which overcame the inability of murine (m)ACE2 to support SARS-CoV-2 infection, was used to show the inability of Type I IFN to control SARS-CoV-2 replication (124). In a similar attempt to overcome the lack of infectability through mACE2, Dinnon et al. recently described a recombinant virus (SARS-CoV-2 MA) with a remodeled S protein mACE2 interface, which replicated in upper and lower airways in young and aged mice with disease being more severe in aged mice. The authors used this model to screen therapeutics from vaccine challenge studies and assessed pegylated IFN-λ-1 as a promising therapeutic. The authors suggested that this model has greater ease of use, cost, and utility over transgenic hACE2 models (125) to evaluate vaccine and therapeutic efficacy in mice (126).\nA preliminary analysis of NK cell function and phenotype has been performed by Zheng et al. using peripheral blood from COVID-19 patients (127). On admission, NK cell levels in the peripheral blood inversely correlated with disease severity. Furthermore, COVID-19 patients with severe disease had significantly lower numbers of circulating NK cells, as compared to mild disease (p \u003c 0.05) (127). Additionally, circulating NK cells in severe disease displayed increased expression of the inhibitory receptor NKG2A and had an hyporesponsive phenotype with lower levels of IFN-γ, tumor necrosis factor (TNF)-α, IL-2, and granzyme B, although degranulation was maintained (127). Finally, as compared to patients with active disease, patients recovering from COVID-19 had higher numbers of NK cells and lower NKG2A expression (127). Liao et al. performed single-cell RNAseq on the cells obtained from bronchoalveolar lavage fluid of severe and mild COVID-19 patients and found that COVID-19 patients had significantly more NK cell infiltrates into the lungs, however patients with severe disease had reduced proportions of NK cells (128). In addition, KLRC1 (NKG2A) and KLRD1 (CD94) were highly expressed by NK cells (128). Carvelli et al. analyzed myeloid and lymphoid populations by immunophenotyping from blood and bronchoalveolar lavage fluid (BALF) in 10 healthy controls, 10 paucisymptomatic COVID-19 patients, 34 pneumonia patients, and 28 patients with ARDS due to SARS-CoV-2 and found that absolute numbers of peripheral blood lymphocytes, including NK cells, were significantly reduced in the pneumonia and ARDS groups compared to healthy controls. Furthermore, the proportion of mature NK cells was reduced in patients with ARDS and NK cells showed increased NKG2A, PD-1, and CD39 (129). Finally, Wilk et al. performed single-cell RNA-sequencing on 7 COVID-19 patients and 6 healthy controls and found that the CD56bright population was depleted in all COVID-19 patients but the CD56dim population was depleted only in patients with severe COVID-19. Furthermore, NK cells had increased expression of the exhaustion markers LAG3 and HAVCR2 (130). NK cell cytopenia seems to be a consistent characteristic among SARS-CoV-2 infected patients (131). Altogether, these data indicate alterations in the NK cell phenotype and functional profile that are consistent with the hypothesis that to establish a productive and lasting infection, SARS-CoV-2 needs to dampen the NK cell response.\nNK cell dysfunctions were also observed in patients from the previous CoV outbreaks. Wang et al. assessed NK cell number and phenotype using peripheral blood from 221 SARS patients admitted to hospitals in Beijing, China (132). NK cell proportion and absolute number were significantly reduced in SARS patients as compared to healthy donors and patients infected with the bacterium Mycoplasma pneumoniae (131). NK cell number correlated inversely with disease severity and patients with anti-SARS CoV-specific IgG or IgM antibodies had significantly fewer NK cells (132). The patients assessed had varied disease duration from 4 to 72 days (mean 31.7 days) and this allowed for patient stratification by disease duration. Within the first 10 days of SARS-CoV-1 infection, NK cell numbers remained high but this period was followed by the development of lymphopenia with levels recovering only around day 40 (132). Dong et al. also observed a reduction of NK cell numbers in SARS patients, and these levels were lower in patients with severe, as compared to mild, SARS (133). In addition, MERS infection is strongly associated with leuko- and lymphopenia (42, 134–136).\nThe mechanisms underlying the reduction of circulating NK cells in patients infected with CoVs are still unclear. As most studies have focused on peripheral blood NK cells, it is possible that the reduced number of circulating NK cells is due to redistribution of blood NK cells into the infected tissues (137). While it is hard to assess NK cell migration to infected tissues in COVID-19 patients, this hypothesis was corroborated by mouse studies, where NK cells have been shown to migrate to the lungs in CoV infected animals (120).\nAn abundance of inhibitory factors, such as TGF-β, may be partially responsible for the NK cell hyporesponsiveness observed in COVID-19 patients. In support of this hypothesis, Huang et al. found significantly higher TGF-β levels in SARS patients compared to healthy controls and this positively correlated with length of stay (138). Given the importance of TGF-β in suppressing NK cell functions, it is possible that the higher levels of TGF-β (as well as other inhibitory cytokines) in CoV patients leads to suppression of NK cell antiviral activity (138). Early studies of COVID-19 patients report secondary (super-) infections, including nosocomial pneumonia or bacteremia as a complication of SARS-CoV-2 infection (138). Since NK cells are critical first responders that play a role in preventing and clearing infections (139), a poor NK cell count or exhausted phenotype, in addition to negatively influencing COVID-19 patient outcomes, could facilitate the development of secondary infections and have a significant negative impact on patient outcomes.\nOne of the main barriers in studying the role of NK cell activation in the early clearance of CoV infection in asymptomatic or mildly symptomatic patients is the fact that these individuals are rarely diagnosed in the clinic and therefore an opportunity to collect samples for research does not exist. Thus, while there is currently no direct evidence to support a role for NK cells in the clearance of SARS-CoV-2, evidence showing that viral infection has a negative effect on the NK cell compartment is accumulating. Given the importance of NK cell activity in early viral clearance and late immunopathology, having a rapid and reliable test to predict NK cell function, such as NKVue™ (ATGen Canada/NKMax), whereby whole blood is stimulated by an NK cell-specific activating cytokine mix and activity is measured via IFN-γ production, might allow researchers to predict who will mount an adequate response with asymptomatic or minimally symptomatic viral clearance and who will need ICU admission, as has been shown with cancer patients (140). Further research will be required into the innate immune response to CoV infection to more fully understand NK cell contributions to viral clearance."}

LitCovid-PubTator

LitCovid-PD-HP

{"project":"LitCovid-PD-HP","denotations":[{"id":"T29","span":{"begin":1257,"end":1264},"obj":"Phenotype"},{"id":"T30","span":{"begin":3251,"end":3256},"obj":"Phenotype"},{"id":"T31","span":{"begin":4089,"end":4098},"obj":"Phenotype"},{"id":"T32","span":{"begin":4272,"end":4281},"obj":"Phenotype"},{"id":"T33","span":{"begin":5554,"end":5564},"obj":"Phenotype"},{"id":"T34","span":{"begin":6014,"end":6025},"obj":"Phenotype"},{"id":"T35","span":{"begin":6303,"end":6314},"obj":"Phenotype"},{"id":"T36","span":{"begin":7519,"end":7528},"obj":"Phenotype"},{"id":"T37","span":{"begin":7532,"end":7542},"obj":"Phenotype"},{"id":"T38","span":{"begin":8950,"end":8956},"obj":"Phenotype"}],"attributes":[{"id":"A29","pred":"hp_id","subj":"T29","obj":"http://purl.obolibrary.org/obo/HP_0020071"},{"id":"A30","pred":"hp_id","subj":"T30","obj":"http://purl.obolibrary.org/obo/HP_0002664"},{"id":"A31","pred":"hp_id","subj":"T31","obj":"http://purl.obolibrary.org/obo/HP_0002090"},{"id":"A32","pred":"hp_id","subj":"T32","obj":"http://purl.obolibrary.org/obo/HP_0002090"},{"id":"A33","pred":"hp_id","subj":"T33","obj":"http://purl.obolibrary.org/obo/HP_0002090"},{"id":"A34","pred":"hp_id","subj":"T34","obj":"http://purl.obolibrary.org/obo/HP_0001888"},{"id":"A35","pred":"hp_id","subj":"T35","obj":"http://purl.obolibrary.org/obo/HP_0001888"},{"id":"A36","pred":"hp_id","subj":"T36","obj":"http://purl.obolibrary.org/obo/HP_0002090"},{"id":"A37","pred":"hp_id","subj":"T37","obj":"http://purl.obolibrary.org/obo/HP_0031864"},{"id":"A38","pred":"hp_id","subj":"T38","obj":"http://purl.obolibrary.org/obo/HP_0002664"}],"text":"NK Cell Role in Clearing Acute Coronavirus Infections\nThere is currently a paucity of studies into the role of NK cells not only in COVID-19 pathophysiology, but also in other coronavirus infections. An in vivo study reported that beige mice on a B6 background cleared SARS-CoV-1 normally, indicating that functional lymphocytes, including NK cells, may not be required to eliminate SARS-CoV-1 in murine models (119). However, in a more recent study characterizing the cellular immune response to SARS-CoV-1 in 12–14-month old BALB/c mice, T cell depletion did not prevent control of SARS-CoV-1 replication (120), suggesting a role for the innate immune system, and NK cells, in viral clearance. Importantly, in this study CD4-depletion resulted in enhanced lung immunopathology and delayed viral clearance, while CD8-depletion did not affect viral replication or clearance, thus highlighting an important role for CD4+ T cells in coronavirus infection. These conflicting results may be due to the inherent limitations of CoV murine models. In 4–8 week-old mice, SARS-CoV-1 is associated only with mild pneumonitis and cytokines are not detectable in the lungs (119, 121, 122). A SARS-CoV-1 isolate (MA-15) replicates to a high titer and is associated with viremia and mortality, however the model lacks significant inflammatory cell infiltration into the lungs (123). Thus, mouse models developed for the study of SARS fell short in terms of reproducing the clinical and histopathological signs of disease (119, 121–123). It is therefore necessary to develop a usable animal model that is capable of reproducing the clinical and histopathological signs on COVID-19. Israelow et al. recently described a SARS-CoV-2 murine model based on adeno associated virus (AAV)9-mediated expression of human (h)ACE2, which replicated the pathologic findings found in COVID-19 patients (124). This model, which overcame the inability of murine (m)ACE2 to support SARS-CoV-2 infection, was used to show the inability of Type I IFN to control SARS-CoV-2 replication (124). In a similar attempt to overcome the lack of infectability through mACE2, Dinnon et al. recently described a recombinant virus (SARS-CoV-2 MA) with a remodeled S protein mACE2 interface, which replicated in upper and lower airways in young and aged mice with disease being more severe in aged mice. The authors used this model to screen therapeutics from vaccine challenge studies and assessed pegylated IFN-λ-1 as a promising therapeutic. The authors suggested that this model has greater ease of use, cost, and utility over transgenic hACE2 models (125) to evaluate vaccine and therapeutic efficacy in mice (126).\nA preliminary analysis of NK cell function and phenotype has been performed by Zheng et al. using peripheral blood from COVID-19 patients (127). On admission, NK cell levels in the peripheral blood inversely correlated with disease severity. Furthermore, COVID-19 patients with severe disease had significantly lower numbers of circulating NK cells, as compared to mild disease (p \u003c 0.05) (127). Additionally, circulating NK cells in severe disease displayed increased expression of the inhibitory receptor NKG2A and had an hyporesponsive phenotype with lower levels of IFN-γ, tumor necrosis factor (TNF)-α, IL-2, and granzyme B, although degranulation was maintained (127). Finally, as compared to patients with active disease, patients recovering from COVID-19 had higher numbers of NK cells and lower NKG2A expression (127). Liao et al. performed single-cell RNAseq on the cells obtained from bronchoalveolar lavage fluid of severe and mild COVID-19 patients and found that COVID-19 patients had significantly more NK cell infiltrates into the lungs, however patients with severe disease had reduced proportions of NK cells (128). In addition, KLRC1 (NKG2A) and KLRD1 (CD94) were highly expressed by NK cells (128). Carvelli et al. analyzed myeloid and lymphoid populations by immunophenotyping from blood and bronchoalveolar lavage fluid (BALF) in 10 healthy controls, 10 paucisymptomatic COVID-19 patients, 34 pneumonia patients, and 28 patients with ARDS due to SARS-CoV-2 and found that absolute numbers of peripheral blood lymphocytes, including NK cells, were significantly reduced in the pneumonia and ARDS groups compared to healthy controls. Furthermore, the proportion of mature NK cells was reduced in patients with ARDS and NK cells showed increased NKG2A, PD-1, and CD39 (129). Finally, Wilk et al. performed single-cell RNA-sequencing on 7 COVID-19 patients and 6 healthy controls and found that the CD56bright population was depleted in all COVID-19 patients but the CD56dim population was depleted only in patients with severe COVID-19. Furthermore, NK cells had increased expression of the exhaustion markers LAG3 and HAVCR2 (130). NK cell cytopenia seems to be a consistent characteristic among SARS-CoV-2 infected patients (131). Altogether, these data indicate alterations in the NK cell phenotype and functional profile that are consistent with the hypothesis that to establish a productive and lasting infection, SARS-CoV-2 needs to dampen the NK cell response.\nNK cell dysfunctions were also observed in patients from the previous CoV outbreaks. Wang et al. assessed NK cell number and phenotype using peripheral blood from 221 SARS patients admitted to hospitals in Beijing, China (132). NK cell proportion and absolute number were significantly reduced in SARS patients as compared to healthy donors and patients infected with the bacterium Mycoplasma pneumoniae (131). NK cell number correlated inversely with disease severity and patients with anti-SARS CoV-specific IgG or IgM antibodies had significantly fewer NK cells (132). The patients assessed had varied disease duration from 4 to 72 days (mean 31.7 days) and this allowed for patient stratification by disease duration. Within the first 10 days of SARS-CoV-1 infection, NK cell numbers remained high but this period was followed by the development of lymphopenia with levels recovering only around day 40 (132). Dong et al. also observed a reduction of NK cell numbers in SARS patients, and these levels were lower in patients with severe, as compared to mild, SARS (133). In addition, MERS infection is strongly associated with leuko- and lymphopenia (42, 134–136).\nThe mechanisms underlying the reduction of circulating NK cells in patients infected with CoVs are still unclear. As most studies have focused on peripheral blood NK cells, it is possible that the reduced number of circulating NK cells is due to redistribution of blood NK cells into the infected tissues (137). While it is hard to assess NK cell migration to infected tissues in COVID-19 patients, this hypothesis was corroborated by mouse studies, where NK cells have been shown to migrate to the lungs in CoV infected animals (120).\nAn abundance of inhibitory factors, such as TGF-β, may be partially responsible for the NK cell hyporesponsiveness observed in COVID-19 patients. In support of this hypothesis, Huang et al. found significantly higher TGF-β levels in SARS patients compared to healthy controls and this positively correlated with length of stay (138). Given the importance of TGF-β in suppressing NK cell functions, it is possible that the higher levels of TGF-β (as well as other inhibitory cytokines) in CoV patients leads to suppression of NK cell antiviral activity (138). Early studies of COVID-19 patients report secondary (super-) infections, including nosocomial pneumonia or bacteremia as a complication of SARS-CoV-2 infection (138). Since NK cells are critical first responders that play a role in preventing and clearing infections (139), a poor NK cell count or exhausted phenotype, in addition to negatively influencing COVID-19 patient outcomes, could facilitate the development of secondary infections and have a significant negative impact on patient outcomes.\nOne of the main barriers in studying the role of NK cell activation in the early clearance of CoV infection in asymptomatic or mildly symptomatic patients is the fact that these individuals are rarely diagnosed in the clinic and therefore an opportunity to collect samples for research does not exist. Thus, while there is currently no direct evidence to support a role for NK cells in the clearance of SARS-CoV-2, evidence showing that viral infection has a negative effect on the NK cell compartment is accumulating. Given the importance of NK cell activity in early viral clearance and late immunopathology, having a rapid and reliable test to predict NK cell function, such as NKVue™ (ATGen Canada/NKMax), whereby whole blood is stimulated by an NK cell-specific activating cytokine mix and activity is measured via IFN-γ production, might allow researchers to predict who will mount an adequate response with asymptomatic or minimally symptomatic viral clearance and who will need ICU admission, as has been shown with cancer patients (140). Further research will be required into the innate immune response to CoV infection to more fully understand NK cell contributions to viral clearance."}

LitCovid-PD-GO-BP

{"project":"LitCovid-PD-GO-BP","denotations":[{"id":"T66","span":{"begin":469,"end":493},"obj":"http://purl.obolibrary.org/obo/GO_0002456"},{"id":"T67","span":{"begin":469,"end":493},"obj":"http://purl.obolibrary.org/obo/GO_0002449"},{"id":"T68","span":{"begin":469,"end":493},"obj":"http://purl.obolibrary.org/obo/GO_0002443"},{"id":"T69","span":{"begin":478,"end":493},"obj":"http://purl.obolibrary.org/obo/GO_0006955"},{"id":"T70","span":{"begin":640,"end":653},"obj":"http://purl.obolibrary.org/obo/GO_0045087"},{"id":"T71","span":{"begin":843,"end":860},"obj":"http://purl.obolibrary.org/obo/GO_0019079"},{"id":"T72","span":{"begin":843,"end":860},"obj":"http://purl.obolibrary.org/obo/GO_0019058"},{"id":"T73","span":{"begin":3257,"end":3265},"obj":"http://purl.obolibrary.org/obo/GO_0070265"},{"id":"T74","span":{"begin":3257,"end":3265},"obj":"http://purl.obolibrary.org/obo/GO_0019835"},{"id":"T75","span":{"begin":3257,"end":3265},"obj":"http://purl.obolibrary.org/obo/GO_0008219"},{"id":"T76","span":{"begin":3257,"end":3265},"obj":"http://purl.obolibrary.org/obo/GO_0001906"},{"id":"T77","span":{"begin":6672,"end":6686},"obj":"http://purl.obolibrary.org/obo/GO_0016477"},{"id":"T78","span":{"begin":7975,"end":7993},"obj":"http://purl.obolibrary.org/obo/GO_0030101"},{"id":"T79","span":{"begin":7978,"end":7993},"obj":"http://purl.obolibrary.org/obo/GO_0001775"},{"id":"T80","span":{"begin":8363,"end":8378},"obj":"http://purl.obolibrary.org/obo/GO_0016032"},{"id":"T81","span":{"begin":9016,"end":9038},"obj":"http://purl.obolibrary.org/obo/GO_0045087"},{"id":"T82","span":{"begin":9023,"end":9038},"obj":"http://purl.obolibrary.org/obo/GO_0006955"}],"text":"NK Cell Role in Clearing Acute Coronavirus Infections\nThere is currently a paucity of studies into the role of NK cells not only in COVID-19 pathophysiology, but also in other coronavirus infections. An in vivo study reported that beige mice on a B6 background cleared SARS-CoV-1 normally, indicating that functional lymphocytes, including NK cells, may not be required to eliminate SARS-CoV-1 in murine models (119). However, in a more recent study characterizing the cellular immune response to SARS-CoV-1 in 12–14-month old BALB/c mice, T cell depletion did not prevent control of SARS-CoV-1 replication (120), suggesting a role for the innate immune system, and NK cells, in viral clearance. Importantly, in this study CD4-depletion resulted in enhanced lung immunopathology and delayed viral clearance, while CD8-depletion did not affect viral replication or clearance, thus highlighting an important role for CD4+ T cells in coronavirus infection. These conflicting results may be due to the inherent limitations of CoV murine models. In 4–8 week-old mice, SARS-CoV-1 is associated only with mild pneumonitis and cytokines are not detectable in the lungs (119, 121, 122). A SARS-CoV-1 isolate (MA-15) replicates to a high titer and is associated with viremia and mortality, however the model lacks significant inflammatory cell infiltration into the lungs (123). Thus, mouse models developed for the study of SARS fell short in terms of reproducing the clinical and histopathological signs of disease (119, 121–123). It is therefore necessary to develop a usable animal model that is capable of reproducing the clinical and histopathological signs on COVID-19. Israelow et al. recently described a SARS-CoV-2 murine model based on adeno associated virus (AAV)9-mediated expression of human (h)ACE2, which replicated the pathologic findings found in COVID-19 patients (124). This model, which overcame the inability of murine (m)ACE2 to support SARS-CoV-2 infection, was used to show the inability of Type I IFN to control SARS-CoV-2 replication (124). In a similar attempt to overcome the lack of infectability through mACE2, Dinnon et al. recently described a recombinant virus (SARS-CoV-2 MA) with a remodeled S protein mACE2 interface, which replicated in upper and lower airways in young and aged mice with disease being more severe in aged mice. The authors used this model to screen therapeutics from vaccine challenge studies and assessed pegylated IFN-λ-1 as a promising therapeutic. The authors suggested that this model has greater ease of use, cost, and utility over transgenic hACE2 models (125) to evaluate vaccine and therapeutic efficacy in mice (126).\nA preliminary analysis of NK cell function and phenotype has been performed by Zheng et al. using peripheral blood from COVID-19 patients (127). On admission, NK cell levels in the peripheral blood inversely correlated with disease severity. Furthermore, COVID-19 patients with severe disease had significantly lower numbers of circulating NK cells, as compared to mild disease (p \u003c 0.05) (127). Additionally, circulating NK cells in severe disease displayed increased expression of the inhibitory receptor NKG2A and had an hyporesponsive phenotype with lower levels of IFN-γ, tumor necrosis factor (TNF)-α, IL-2, and granzyme B, although degranulation was maintained (127). Finally, as compared to patients with active disease, patients recovering from COVID-19 had higher numbers of NK cells and lower NKG2A expression (127). Liao et al. performed single-cell RNAseq on the cells obtained from bronchoalveolar lavage fluid of severe and mild COVID-19 patients and found that COVID-19 patients had significantly more NK cell infiltrates into the lungs, however patients with severe disease had reduced proportions of NK cells (128). In addition, KLRC1 (NKG2A) and KLRD1 (CD94) were highly expressed by NK cells (128). Carvelli et al. analyzed myeloid and lymphoid populations by immunophenotyping from blood and bronchoalveolar lavage fluid (BALF) in 10 healthy controls, 10 paucisymptomatic COVID-19 patients, 34 pneumonia patients, and 28 patients with ARDS due to SARS-CoV-2 and found that absolute numbers of peripheral blood lymphocytes, including NK cells, were significantly reduced in the pneumonia and ARDS groups compared to healthy controls. Furthermore, the proportion of mature NK cells was reduced in patients with ARDS and NK cells showed increased NKG2A, PD-1, and CD39 (129). Finally, Wilk et al. performed single-cell RNA-sequencing on 7 COVID-19 patients and 6 healthy controls and found that the CD56bright population was depleted in all COVID-19 patients but the CD56dim population was depleted only in patients with severe COVID-19. Furthermore, NK cells had increased expression of the exhaustion markers LAG3 and HAVCR2 (130). NK cell cytopenia seems to be a consistent characteristic among SARS-CoV-2 infected patients (131). Altogether, these data indicate alterations in the NK cell phenotype and functional profile that are consistent with the hypothesis that to establish a productive and lasting infection, SARS-CoV-2 needs to dampen the NK cell response.\nNK cell dysfunctions were also observed in patients from the previous CoV outbreaks. Wang et al. assessed NK cell number and phenotype using peripheral blood from 221 SARS patients admitted to hospitals in Beijing, China (132). NK cell proportion and absolute number were significantly reduced in SARS patients as compared to healthy donors and patients infected with the bacterium Mycoplasma pneumoniae (131). NK cell number correlated inversely with disease severity and patients with anti-SARS CoV-specific IgG or IgM antibodies had significantly fewer NK cells (132). The patients assessed had varied disease duration from 4 to 72 days (mean 31.7 days) and this allowed for patient stratification by disease duration. Within the first 10 days of SARS-CoV-1 infection, NK cell numbers remained high but this period was followed by the development of lymphopenia with levels recovering only around day 40 (132). Dong et al. also observed a reduction of NK cell numbers in SARS patients, and these levels were lower in patients with severe, as compared to mild, SARS (133). In addition, MERS infection is strongly associated with leuko- and lymphopenia (42, 134–136).\nThe mechanisms underlying the reduction of circulating NK cells in patients infected with CoVs are still unclear. As most studies have focused on peripheral blood NK cells, it is possible that the reduced number of circulating NK cells is due to redistribution of blood NK cells into the infected tissues (137). While it is hard to assess NK cell migration to infected tissues in COVID-19 patients, this hypothesis was corroborated by mouse studies, where NK cells have been shown to migrate to the lungs in CoV infected animals (120).\nAn abundance of inhibitory factors, such as TGF-β, may be partially responsible for the NK cell hyporesponsiveness observed in COVID-19 patients. In support of this hypothesis, Huang et al. found significantly higher TGF-β levels in SARS patients compared to healthy controls and this positively correlated with length of stay (138). Given the importance of TGF-β in suppressing NK cell functions, it is possible that the higher levels of TGF-β (as well as other inhibitory cytokines) in CoV patients leads to suppression of NK cell antiviral activity (138). Early studies of COVID-19 patients report secondary (super-) infections, including nosocomial pneumonia or bacteremia as a complication of SARS-CoV-2 infection (138). Since NK cells are critical first responders that play a role in preventing and clearing infections (139), a poor NK cell count or exhausted phenotype, in addition to negatively influencing COVID-19 patient outcomes, could facilitate the development of secondary infections and have a significant negative impact on patient outcomes.\nOne of the main barriers in studying the role of NK cell activation in the early clearance of CoV infection in asymptomatic or mildly symptomatic patients is the fact that these individuals are rarely diagnosed in the clinic and therefore an opportunity to collect samples for research does not exist. Thus, while there is currently no direct evidence to support a role for NK cells in the clearance of SARS-CoV-2, evidence showing that viral infection has a negative effect on the NK cell compartment is accumulating. Given the importance of NK cell activity in early viral clearance and late immunopathology, having a rapid and reliable test to predict NK cell function, such as NKVue™ (ATGen Canada/NKMax), whereby whole blood is stimulated by an NK cell-specific activating cytokine mix and activity is measured via IFN-γ production, might allow researchers to predict who will mount an adequate response with asymptomatic or minimally symptomatic viral clearance and who will need ICU admission, as has been shown with cancer patients (140). Further research will be required into the innate immune response to CoV infection to more fully understand NK cell contributions to viral clearance."}

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