Abstract
Corona virus disease 2019 (COVID-19) pathogenesis is intimately linked to the severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) and disease severity has been associated with compromised induction of type I interferon (IFN-I) cytokines which coordinate the innate immune response to virus infections. Here we identified the SARS-CoV-2 encoded protein, Spike, as an inhibitor of IFN-I that antagonizes viral RNA pattern recognition receptor RIG-I signaling. Ectopic expression of SARS-CoV-2 Spike blocked RIG-I mediated activation of IFNβ and downstream induction of interferon stimulated genes. Consequently, SARS-CoV-2 Spike expressing cells harbored increased RNA viral burden compared to control cells. Co-immunoprecipitation experiments revealed SARS-CoV-2 Spike associated with interferon regulatory factor 3 (IRF3), a key transcription factor that governs IFN-I activation. Co-expression analysis via immunoassays further indicated Spike specifically suppressed IRF3 expression as NF-κB and STAT1 transcription factor levels remained intact. Further biochemical experiments uncovered SARS-CoV-2 Spike potentiated proteasomal degradation of IRF3, implicating a novel mechanism by which SARS-CoV-2 evades the host innate antiviral immune response to facilitate COVID-19 pathogenesis.
Highlights
Severe acute respiratory syndrome Corona virus 2 (SARS-CoV-2) is a newly emerged pathogen and is associated with Corona virus disease 19 (COVID-19) which can manifest into life threatening upper respiratory pathologies and lung dysfunctions in severely affected individuals (V’kovski et al, 2021)
As poly (I:C) mediated activation of IFNb was suppressed by SARSCoV-2 Spike, downstream activation of the IFN stimulated response element (ISRE) luciferase reporter and expression of IFN stimulated genes (ISGs) CCL5 (RANTES), CXCL10 (IP-10), and IFIT2 (ISG54) were inhibited by Spike as well (Figures 1C–F)
SARS-CoV-2 Spike binds to the angiotensin-converting enzyme 2 (ACE2) receptor on host cells and in conjunction with the transmembrane protease serine 2 (TMPRSS2) found on the host cell membrane, mediates viral entry into the cell (Huang et al, 2020; V’kovski et al, 2021)
Summary
Severe acute respiratory syndrome Corona virus 2 (SARS-CoV-2) is a newly emerged pathogen and is associated with Corona virus disease 19 (COVID-19) which can manifest into life threatening upper respiratory pathologies and lung dysfunctions in severely affected individuals (V’kovski et al, 2021). Innate immunity provides a first line of defense against invading pathogens including viruses in which the induction of type I interferon (IFN-I) cytokines (IFNa/b) plays an essential role in limiting virus replication and spread (Gonzales-van Horn and Farrar, 2015; Ghosh et al, 2016). While IFN-I is regulated at the level of transcription, primarily by the interferon regulatory factor 3 (IRF3) transcription factor, IRF3 activation itself requires engagement of upstream pattern recognition receptors (PRRs) in cells of the innate immune system. IFNAR ligation results in the activation of a Janus kinase/Signal transducer and activator of transcription (JAK/STAT) pathway that culminates in the formation of a STAT1/STAT2/IRF9 heterotrimeric transcription factor which binds to IFN stimulated response elements (ISRE) found on the promoters and enhancers of IFN stimulated genes (ISGs). ISGs operate as effectors and restriction factors that directly or indirectly target the virus or at various stages of its replication cycle (Akira et al, 2006; Pandey et al, 2014)
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