内部收益率3
干扰素
生物
冠状病毒
病毒学
细胞生物学
效应器
融合蛋白
免疫学
免疫系统
先天免疫系统
医学
基因
2019年冠状病毒病(COVID-19)
重组DNA
疾病
传染病(医学专业)
遗传学
病理
作者
Xiaoman Liu,Wei Liang,Feifei Xu,Fei Zhao,Haibin Yu,Zhangling Fan,Shan Mei,Yuling Hu,Linxuan Zhai,Justin Guo,Ai Zheng,Shan Cen,Chen Liang,Fei Guo
出处
期刊:Science Signaling
[American Association for the Advancement of Science (AAAS)]
日期:2022-04-12
卷期号:15 (729)
被引量:53
标识
DOI:10.1126/scisignal.abg8744
摘要
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the unprecedented coronavirus disease 2019 (COVID-19) pandemic. Critical cases of COVID-19 are characterized by the production of excessive amounts of cytokines and extensive lung damage, which is partially caused by the fusion of SARS-CoV-2-infected pneumocytes. Here, we found that cell fusion caused by the SARS-CoV-2 spike (S) protein induced a type I interferon (IFN) response. This function of the S protein required its cleavage by proteases at the S1/S2 and the S2' sites. We further showed that cell fusion damaged nuclei and resulted in the formation of micronuclei that were sensed by the cytosolic DNA sensor cGAS and led to the activation of its downstream effector STING. Phosphorylation of the transcriptional regulator IRF3 and the expression of IFNB, which encodes a type I IFN, were abrogated in cGAS-deficient fused cells. Moreover, infection with VSV-SARS-CoV-2 also induced cell fusion, DNA damage, and cGAS-STING-dependent expression of IFNB. Together, these results uncover a pathway underlying the IFN response to SARS-CoV-2 infection. Our data suggest a mechanism by which fused pneumocytes in the lungs of patients with COVID-19 may enhance the production of IFNs and other cytokines, thus exacerbating disease severity.
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