期刊
CELL REPORTS
卷 34, 期 7, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2021.108761
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资金
- National Key Research and Development Program of China [2018YFA0900404]
- National Natural Science Foundation of China [31870864]
- National Science Foundation for Young Scientists of China [31901011]
- Fundamental Research Funds for the Provincial Universities of Zhejiang [RF-B2020003]
- Zhejiang University of Technology
SARS-CoV-2 activates and represses the innate immune response, leading to dysregulation and delayed interferon expression, which contribute to the development of COVID-19. The study reveals that ORF9b inhibits the type I interferon response during SARS-CoV-2 infection.
Coronavirus disease 2019 (COVID-19) is a current global health threat caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Emerging evidence indicates that SARS-CoV-2 elicits a dysregulated immune response and a delayed interferon (IFN) expression in patients, which contribute largely to the viral pathogenesis and development of COVID-19. However, underlying mechanisms remain to be elucidated. Here, we report the activation and repression of the innate immune response by SARS-CoV-2. We show that SARS-CoV-2 RNA activates the RIG-I-MAVS-dependent IFN signaling pathway. We further uncover that ORF9b immediately accumulates and antagonizes the antiviral type I IFN response during SARS-CoV-2 infection on primary human pulmonary alveolar epithelial cells. ORF9b targets the nuclear factor kappa B (NF-kappa B) essential modulator NEMO and interrupts its K63-linked polyubiquitination upon viral stimulation, thereby inhibiting the canonical IkB kinase alpha (IKK alpha)/beta/gamma-NF-kappa B signaling and subsequent IFN production. Our findings thus unveil the innate immunosuppression by ORF9b and provide insights into the host-virus interplay during the early stage of SARS-CoV-2 infection.
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