Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Membrane (M) and Spike (S) Proteins Antagonize Host Type I Interferon Response

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread worldwide and has infected more than 250 million people. A typical feature of COVID-19 is the lack of type I interferon (IFN-I)-mediated antiviral immunity in patients. However, the detailed molecular mechanisms by which SARS-CoV-2 evades the IFN-I-mediated antiviral response remain elusive. Here, we performed a comprehensive screening and identified a set of SARS-CoV-2 proteins that antagonize the IFN-I response. Subsequently, we characterized the mechanisms of two viral proteins antagonize IFN-I production and downstream signaling. SARS-CoV-2 membrane protein binds to importin karyopherin subunit alpha-6 (KPNA6) to inhibit interferon regulatory factor 3(IRF3) nuclear translocation. Further, the spike protein interacts with signal transducer and activator of transcription 1 (STAT1) to block its association with Janus kinase 1 (JAK1). This study increases our understanding of SARS-CoV-2 pathogenesis and suggests novel therapeutic targets for the treatment of COVID-19.

Reduced interferon antagonism but similar drug sensitivity in Omicron variant compared to Delta variant SARS-CoV-2 isolates

“…Taken together, these data show that Omicron viruses are less effective than Delta viruses in antagonising the interferon response in human cells, which may contribute to the lower pathogenicity of the Omicron variant observed in patients [21,22]. Notably, SARS-CoV-2 proteins known to inhibit the host cell interferon response including S, NSP3, NSP6, NSP14, nucleocapsid (N), and membrane (M) are mutated in the Omicron variant [23,24].…”

ORF6 protein of SARS-CoV-2 inhibits TRIM25 mediated RIG-I ubiquitination to mitigate type I IFN induction

“…Apart from the earlier 4 proteins, a few additional proteins also inhibited IFN induction (NSP5) or signaling (NSP7, NSP9, ORF9b), though less effectively (Sup Fig 1B). To further substantiate our results, we compiled and compared the data from previous studies where similar reporter-based approaches were utilized to screen for IFN antagonists of SARS-CoV-2 (Fig 1C, D) (Lei et al ., 2020), (Li et al , 2020), (Xia et al ., 2020), (Yuen et al , 2020), (Zhang et al , 2021), (Hayn et al , 2021), (Stukalov et al , 2021), (Shemesh et al , 2021), (Fu et al , 2021). Our findings largely corroborated other studies, and this comparison revealed ORF6 as the most consistent and effective inhibitor of IFN induction and ISG signaling across various studies (Fig 1D) (Lei et al ., 2020), (Li et al ., 2020), (Xia et al ., 2020), (Yuen et al ., 2020), (Zhang et al ., 2021), (Vazquez et al , 2021), (Hayn et al ., 2021), (Stukalov et al ., 2021).…”

Dysregulated Interferon Response and Immune Hyperactivation in Severe COVID-19: Targeting STATs as a Novel Therapeutic Strategy

“…observed that the SARS-CoV-2 M protein did not significantly affect IRF3 phosphorylation, but blocked its nuclear translocation. Likewise, the S protein was found to suppress STAT1 phosphorylation and nuclear translocation by intervening with JAK1-STAT1 interaction ( 56 ). On the other hand, without directly influencing STAT1 and STAT2 activation, nsp7 and ORF7a clearly inhibited ISRE promoter activity ( 56 ).…”

“…Likewise, the S protein was found to suppress STAT1 phosphorylation and nuclear translocation by intervening with JAK1-STAT1 interaction ( 56 ). On the other hand, without directly influencing STAT1 and STAT2 activation, nsp7 and ORF7a clearly inhibited ISRE promoter activity ( 56 ). Nsp9 and ORF8 exhibited inhibition of STAT1 activation, whereas Helicase and E protein intervened with STAT1 and STAT2 activation ( 56 ).…”