SARS-CoV-2 ORF9b antagonizes type I and III interferons by targeting multiple components of the RIG-I/MDA-5-MAVS, TLR3-TRIF, and cGAS-STING signaling pathways.
The suppression of types I and III interferon (IFN) responses by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contributes to the pathogenesis of coronavirus disease 2019 (COVID-19). The strategy used by SARS-CoV-2 to evade antiviral immunity needs further investigation. Here, we reported that SARS-CoV-2 ORF9b inhibited types I and III ... IFN production by targeting multiple molecules of innate antiviral signaling pathways. SARS-CoV-2 ORF9b impaired the induction of types I and III IFNs by Sendai virus and poly (I:C). SARS-CoV-2 ORF9b inhibited the activation of types I and III IFNs induced by the components of cytosolic dsRNA-sensing pathways of RIG-I/MDA5-MAVS signaling, including RIG-I, MDA-5, MAVS, TBK1, and IKK?, rather than IRF3-5D, which is the active form of IRF3. SARS-CoV-2 ORF9b also suppressed the induction of types I and III IFNs by TRIF and STING, which are the adaptor protein of the endosome RNA-sensing pathway of TLR3-TRIF signaling and the adaptor protein of the cytosolic DNA-sensing pathway of cGAS-STING signaling, respectively. A mechanistic analysis revealed that the SARS-CoV-2 ORF9b protein interacted with RIG-I, MDA-5, MAVS, TRIF, STING, and TBK1 and impeded the phosphorylation and nuclear translocation of IRF3. In addition, SARS-CoV-2 ORF9b facilitated the replication of the vesicular stomatitis virus. Therefore, the results showed that SARS-CoV-2 ORF9b negatively regulates antiviral immunity and thus facilitates viral replication. This study contributes to our understanding of the molecular mechanism through which SARS-CoV-2 impairs antiviral immunity and provides an essential clue to the pathogenesis of COVID-19.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Adaptor Proteins, Vesicular Transport, Animals, Chlorocebus aethiops, Coronavirus Nucleocapsid Proteins, DEAD Box Protein 58, Gene Expression Regulation, HEK293 Cells, HeLa Cells, Humans, I-kappa B Kinase, Immune Evasion, Immunity, Innate, Interferon Regulatory Factor-3, Interferon-Induced Helicase, IFIH1, Interferons, Membrane Proteins, Nucleotidyltransferases, Phosphoproteins, Plasmids, Protein Serine-Threonine Kinases, Receptors, Immunologic, SARS-CoV-2, Signal Transduction, Toll-Like Receptor 3, Transfection, Vero Cells, Virus Replication
Adaptor Proteins, Signal Transducing, Adaptor Proteins, Vesicular Transport, Animals, Chlorocebus aethiops, Coronavirus Nucleocapsid Proteins, DEAD Box Protein 58, Gene Expression Regulation, HEK293 Cells, HeLa Cells, Humans, I-kappa B Kinase, Immune Evasion, Immunity, Innate, Interferon Regulatory Factor-3, Interferon-Induced Helicase, IFIH1, Interferons, Membrane Proteins, Nucleotidyltransferases, Phosphoproteins, Plasmids, Protein Serine-Threonine Kinases, Receptors, Immunologic, SARS-CoV-2, Signal Transduction, Toll-Like Receptor 3, Transfection, Vero Cells, Virus Replication
J Med Virol
Date: Dec. 01, 2020
PubMed ID: 33913550
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