Abstract
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 IKKε, 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.
Keywords:
COVID-19; IFNs; ORF9b; SARS-CoV-2; antiviral immunity.
© 2021 Wiley Periodicals LLC.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adaptor Proteins, Signal Transducing / genetics
-
Adaptor Proteins, Signal Transducing / immunology
-
Adaptor Proteins, Vesicular Transport / genetics
-
Adaptor Proteins, Vesicular Transport / immunology
-
Animals
-
Chlorocebus aethiops
-
Coronavirus Nucleocapsid Proteins / genetics
-
Coronavirus Nucleocapsid Proteins / immunology
-
DEAD Box Protein 58 / genetics
-
DEAD Box Protein 58 / immunology*
-
Gene Expression Regulation
-
HEK293 Cells
-
HeLa Cells
-
Humans
-
I-kappa B Kinase / genetics
-
I-kappa B Kinase / immunology
-
Immune Evasion / genetics*
-
Immunity, Innate
-
Interferon Regulatory Factor-3 / genetics
-
Interferon Regulatory Factor-3 / immunology
-
Interferon-Induced Helicase, IFIH1 / genetics
-
Interferon-Induced Helicase, IFIH1 / immunology
-
Interferons / genetics
-
Interferons / immunology*
-
Membrane Proteins / genetics
-
Membrane Proteins / immunology
-
Nucleotidyltransferases / genetics
-
Nucleotidyltransferases / immunology*
-
Phosphoproteins / genetics
-
Phosphoproteins / immunology
-
Plasmids / chemistry
-
Plasmids / metabolism
-
Protein Serine-Threonine Kinases / genetics
-
Protein Serine-Threonine Kinases / immunology
-
Receptors, Immunologic / genetics
-
Receptors, Immunologic / immunology*
-
SARS-CoV-2 / genetics
-
SARS-CoV-2 / immunology*
-
SARS-CoV-2 / pathogenicity
-
Signal Transduction / genetics
-
Signal Transduction / immunology
-
Toll-Like Receptor 3 / genetics
-
Toll-Like Receptor 3 / immunology*
-
Transfection
-
Vero Cells
-
Virus Replication / immunology
Substances
-
Adaptor Proteins, Signal Transducing
-
Adaptor Proteins, Vesicular Transport
-
Coronavirus Nucleocapsid Proteins
-
IRF3 protein, human
-
Interferon Regulatory Factor-3
-
MAVS protein, human
-
Membrane Proteins
-
Phosphoproteins
-
Receptors, Immunologic
-
STING1 protein, human
-
TICAM1 protein, human
-
TLR3 protein, human
-
Toll-Like Receptor 3
-
nucleocapsid phosphoprotein, SARS-CoV-2
-
Interferons
-
Protein Serine-Threonine Kinases
-
TBK1 protein, human
-
I-kappa B Kinase
-
Nucleotidyltransferases
-
cGAS protein, human
-
RIGI protein, human
-
IFIH1 protein, human
-
DEAD Box Protein 58
-
Interferon-Induced Helicase, IFIH1