SARS-CoV-2 spike protein-induced cell fusion activates the cGAS-STING pathway and the interferon response

• Published in: Science signaling 2022-04, Vol.15 (729), p.eabg8744-eabg8744
• Main Authors: Liu, Xiaoman, Wei, Liang, Xu, Fengwen, Zhao, Fei, Huang, Yu, Fan, Zhangling, Mei, Shan, Hu, Yamei, Zhai, Linxuan, Guo, Justin, Zheng, Aihua, Cen, Shan, Liang, Chen, Guo, Fei
• Format: Article
• Language: English
• Subjects: ACE2; Adaptor proteins; Angiotensin-converting enzyme 2; Cell activation; Cell Fusion; Coronaviruses; COVID-19; COVID-19 - genetics; Cytokines; Damage; Deoxyribonucleic acid; DNA; DNA damage; Epithelial cells; Epithelium; Fusion protein; Gene expression; Genes; Humans; Inflammation; Inflammatory response; Interferon; Interferon Type I - genetics; Lungs; Micronuclei; Nucleotidyltransferases - genetics; Nucleotidyltransferases - metabolism; Pneumocytes; Proteins; SARS-CoV-2; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - genetics; Spike Glycoprotein, Coronavirus - metabolism; Spike protein; Viral diseases
• ISSN: 1945-0877; 1937-9145
• DOI: 10.1126/scisignal.abg8744

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 , 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 . 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.