Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Membrane (M) Protein Inhibits Type I and III Interferon Production by Targeting RIG-I/MDA-5 Signaling

Abstract

The coronavirus disease 2019 (COVID-19) caused by Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has quickly spread worldwide and has infected more than ten million individuals. One of the typical features of COVID-19 is that both type I and III interferon (IFN)-mediated antiviral immunity are suppressed. However, the molecular mechanism by which SARS-CoV-2 evades this antiviral immunity remains elusive. Here, we report that the SARS-CoV-2 membrane (M) protein inhibits the production of type I and III IFNs induced by the cytosolic dsRNA-sensing pathway of RIG-I/MDA-5-MAVS signaling. The SARS-CoV2 M protein also dampens type I and III IFN induction stimulated by Sendai virus infection or poly (I:C) transfection. Mechanistically, the SARS-CoV-2 M protein interacts with RIG-I, MAVS, and TBK1 and prevents the formation of a multi-protein complex containing RIG-I, MAVS, TRAF3, and TBK1, thus impeding IRF3 phosphorylation, nuclear translocation, and activation. Consequently, the ectopic expression of the SARS-CoV2 M protein facilitates the replication of vesicular stomatitis virus (VSV). Taken together, the SARS-CoV-2 M protein antagonizes type I and III IFN production by targeting RIG-I/MDA-5 signaling, which subsequently attenuates antiviral immunity and enhances viral replication. This study provides insight into the interpretation of the SARS-CoV-2-induced antiviral immune suppression and sheds light on the pathogenic mechanism of COVID-19.

SARS-CoV-2 ORF9b Antagonizes Type I and III Interferons by Targeting Multiple Components of RIG-I/MDA-5-MAVS, TLR3-TRIF, and cGAS-STING Signaling Pathways

“…For the inhibition of TLR3-TRIF signaling, SARS-CoV-2 ORF9b can only target TRIF but does not have any effect on TRIF-induced TBK1 phosphorylation, suggesting that the inhibitory effect of SARS-CoV-2 ORF9b on TRIF-induced IFN signaling activation is achieved by interacting with TRIF directly but not by affecting TBK1 phosphorylation. In addition, the M protein of both SARS-COV-1 and 2 can inhibit IFN production by targeting RIG-I/MDA-5 signaling but have no effect on TBK1 phosphorylation; 34,40 thus, the inhibition of TBK1 phosphorylation is not required for the antagonizing of IFNs by these viral proteins. Overexpression of SARS-CoV-2 ORF9b can inhibit IRF3 phosphorylation induced by RIG-IN, MAVS, STING, TRIF, and SeV infection, thus the inhibition of IRF3 phosphorylation may be indispensable for IFN antagonizing by these viral proteins.…”

“…The plaques on the monolayer were used to determine the titer of VSV-eGFP as described in our previous publications. 34…”

Reply to Dorgham et al., “Considering Personalized Interferon Beta Therapy for COVID-19”

“…The culprit proteins (like NSP-type and ORF-type proteins) of the virus can antagonize the production of IFNs, so SARS-CoV-2 could evade innate immune system[6]. Same findings have been reported[7][8]. InDorgham et al study, Covid-19 patients with increased serum IFN-β level experienced significantly higher mortality.…”

Immunotoxic role of organophosphates: An unseen risk escalating SARS-CoV-2 pathogenicity

“…In addition, other SARS-CoV-2 proteins like NSP13, NSP14, NSP15 and ORF6 have been suggested to antagonize IFN function by suppressing nuclear localization of IRF3 ( Yuen et al, 2020 ). Notably, viral M protein interacts with RIG-1/MDA-5-MAVS signaling pathway to hinder IFN-I and IFN-III production ( Zheng et al, 2020 ). Interestingly, certain essential oil components such as (E,E)-α-farnesene, (E,E)-farnesol, and (E)-nerolidol have better binding affinity for SARS-CoV-2 proteins like Mpro and hence could be effective in preventing viral proliferation.…”