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
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
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SARS-CoV-2 ORF9b 通过靶向 RIG-I/MDA-5-MAVS、TLR3-TRIF 和 cGAS-STING 信号通路的多个成分来拮抗 I 型和 III 型干扰素
DOI：
10.1002/jmv.27050
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发表时间：
2021-05-09
影响因子：
12.7
通讯作者：
Wang, Pei-Hui
中科院分区：
文献类型：
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作者：
Han, Lulu;Zhuang, Meng-Wei;Wang, Pei-Hui
严重急性呼吸综合征冠状病毒2(SARS-CoV-2)对I型和III型干扰素反应的抑制是冠状病毒病2019年(新冠肺炎)的发病机制之一。SARS-CoV-2用来逃避抗病毒免疫的策略需要进一步调查。在这里，我们报道了SARS-CoV-2 ORF9b通过靶向多个天然抗病毒信号通路分子来抑制I型和III型干扰素的产生。SARS-CoV-2 ORF9b减弱仙台病毒和Poly(I：C)诱导的I型和III型IFN。SARS-CoV-2 ORF9b抑制RIG-I/MDA5-MAVS信号的胞质dsRNA敏感通路成分RIG-I、MDA-5、MAVS、TBK1和IKK epsilon诱导的I型和III型IFN的激活，而不是IRF3的活性形式IRF3-5D。SARS-CoV-2 ORF9b还抑制了TLR3-TRIF信号的内体RNA传感通路的适配蛋白TRIF和cGAS-STIN信号的胞质DNA传感通路的适配蛋白TRIF和TING对I型和III型IFN的诱导作用。机制分析表明，SARS-CoV-2 ORF9b蛋白与RIG-I、MDA-5、MAVS、TRIF、STING和TBK1相互作用，阻碍IRF3的磷酸化和核转位。此外，SARS-CoV-2 ORF9b促进水疱性口炎病毒的复制。因此，结果表明SARS-CoV-2 ORF9b负性调节抗病毒免疫，从而促进病毒复制。这项研究有助于我们了解SARS-CoV-2损害抗病毒免疫的分子机制，并为新冠肺炎的发病机制提供必要的线索。
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 epsilon, 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.