PMC:7200337 / 11403-13171 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7200337","sourcedb":"PMC","sourceid":"7200337","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7200337","text":"Imbalance between Antiviral and Proinflammatory Responses\nTaken together, the multiplicity of strategies developed by pathogenic CoVs to escape immune sensing, particularly the IFN-I pathway, suggests a critical role played by the dysregulation of IFN-I response in COVID-19 pathogenicity. Concordantly, animal models of SARS-CoV-1 and MERS-CoV infection indicate that failure to elicit an early IFN-I response correlates with the severity of disease (Channappanavar et al., 2016). Perhaps more importantly, these models demonstrate that timing is key, as IFN is protective early in disease but later becomes pathologic (Channappanavar et al., 2016, Channappanavar et al., 2019). Perhaps interferon-induced upregulation of ACE2 in airway epithelia may contribute to this effect (Ziegler et al., 2020). Furthermore, while pathogenic CoVs block IFN signaling, they may actively promote other inflammatory pathways contributing to pathology. For instance, SARS-CoV-1 ORF3a, ORF8b, and E proteins enhance inflammasome activation (Chen et al., 2019, Nieto-Torres et al., 2015, Shi et al., 2019, Siu et al., 2019), leading to secretion of IL-1β and IL-18, which are likely to contribute to pathological inflammation. Similarly, SARS-CoV-2 NSP9 and NSP10 might induce IL-6 and IL-8 production, potentially by inhibition of NKRF, an endogenous NF-kB repressor (Li et al., 2020a). Collectively, these proinflammatory processes likely contribute to the “cytokine storm” observed in COVID-19 patients and substantiate a role for targeted immunosuppressive treatment regimens. Moving forward, a clear understanding of the delicate balance between antiviral and inflammatory innate immune programs will be essential to developing effective biomarkers and therapeutics for 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