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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.
Han, Lulu; Zhuang, Meng-Wei; Deng, Jian; Zheng, Yi; Zhang, Jing; Nan, Mei-Ling; Zhang, Xue-Jing; Gao, Chengjiang; Wang, Pei-Hui.
  • Han L; Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
  • Zhuang MW; Key Laboratory for Experimental Teratology of Ministry of Education and Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
  • Deng J; Key Laboratory for Experimental Teratology of Ministry of Education and Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
  • Zheng Y; Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
  • Zhang J; Key Laboratory for Experimental Teratology of Ministry of Education and Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
  • Nan ML; Key Laboratory for Experimental Teratology of Ministry of Education and Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
  • Zhang XJ; Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
  • Gao C; Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
  • Wang PH; Key Laboratory for Experimental Teratology of Ministry of Education and Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
J Med Virol ; 93(9): 5376-5389, 2021 09.
Article in English | MEDLINE | ID: covidwho-1206842
Semantic information from SemMedBD (by NLM)
1. 2019 novel coronavirus CAUSES COVID-19
Subject
2019 novel coronavirus
Predicate
CAUSES
Object
COVID-19
2. Adaptor Protein AUGMENTS C0036658
Subject
Adaptor Protein
Predicate
AUGMENTS
Object
C0036658
3. STING1 gene DISRUPTS Phosphorylation
Subject
STING1 gene
Predicate
DISRUPTS
Object
Phosphorylation
4. STING1 gene DISRUPTS Nuclear Translocation
Subject
STING1 gene
Predicate
DISRUPTS
Object
Nuclear Translocation
5. 2019 novel coronavirus CAUSES COVID-19
Subject
2019 novel coronavirus
Predicate
CAUSES
Object
COVID-19
6. Adaptor Proteins, Signal Transducing AUGMENTS Esthesia
Subject
Adaptor Proteins, Signal Transducing
Predicate
AUGMENTS
Object
Esthesia
7. STING1 gene DISRUPTS Phosphorylation
Subject
STING1 gene
Predicate
DISRUPTS
Object
Phosphorylation
8. STING1 gene DISRUPTS Nuclear Translocation
Subject
STING1 gene
Predicate
DISRUPTS
Object
Nuclear Translocation
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 (IC). 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.
Subject(s)
Keywords

Full text: Available Collection: International databases Database: MEDLINE Main subject: Receptors, Immunologic / Interferons / Toll-Like Receptor 3 / Immune Evasion / DEAD Box Protein 58 / SARS-CoV-2 / Nucleotidyltransferases Language: English Journal: J Med Virol Year: 2021 Document Type: Article Affiliation country: Jmv.27050

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Receptors, Immunologic / Interferons / Toll-Like Receptor 3 / Immune Evasion / DEAD Box Protein 58 / SARS-CoV-2 / Nucleotidyltransferases Language: English Journal: J Med Virol Year: 2021 Document Type: Article Affiliation country: Jmv.27050