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

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

  • Sci Signal. 2022 Apr 12;15(729):eabg8744. doi: 10.1126/scisignal.abg8744.
Xiaoman Liu 1,  Liang Wei 1,  Fengwen Xu 1,  Fei Zhao 1,  Yu Huang 1,  Zhangling Fan 1,  Shan Mei 1,  Yamei Hu 1,  Linxuan Zhai 2,  Justin Guo 3,  Aihua Zheng 4,  Shan Cen 5,  Chen Liang 6,  Fei Guo 1
Affiliations

Affiliations

  • 1 National Health Commission of the People's Republic of China Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology and Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
  • 2 Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 3 International Division, High School Affiliated to Renmin University of China, Beijing 100080, China.
  • 4 State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100730, China.
  • 5 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
  • 6 McGill University AIDS Centre, Lady Davis Institute, Jewish General Hospital, Montreal H3T 1E2, Canada.
PMID: 35412852 DOI: 10.1126/scisignal.abg8744
Abstract

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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