SARS-CoV-2 triggers inflammatory responses and cell death through caspase-8 activation

  • Signal Transduct Target Ther. 2020 Oct 9;5(1):235. doi: 10.1038/s41392-020-00334-0.
Shufen Li   #  1 ,  Yulan Zhang   #  1 ,  Zhenqiong Guan   #  1  2 ,  Huiling Li  1  2 ,  Meidi Ye  1  2 ,  Xi Chen  3 ,  Jun Shen  4 ,  Yiwu Zhou  5 ,  Zheng-Li Shi  1  2 ,  Peng Zhou  6  7 ,  Ke Peng  8  9
Affiliations
  • 1. State Key Laboratory of Virology, CAS Key Laboratory of Special Pathogens, Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China.
  • 2. University of Chinese Academy of Sciences, Beijing, China.
  • 3. Department of Thoracic and Vascular Surgery, Wuhan No. 1 Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  • 4. Infectious Disease Department, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, 201102, China.
  • 5. Department of Forensic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Hangkong Road, Wuhan, 430074, China.
  • 6. State Key Laboratory of Virology, CAS Key Laboratory of Special Pathogens, Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China. [email protected].
  • 7. University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • 8. State Key Laboratory of Virology, CAS Key Laboratory of Special Pathogens, Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China. [email protected].
  • 9. University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 33037188 DOI: 10.1038/s41392-020-00334-0
Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Infection can lead to respiratory illness and multi-organ failure in critically ill patients. Although the virus-induced lung damage and inflammatory cytokine storm are believed to be directly associated with coronavirus disease 2019 (COVID-19) clinical manifestations, the underlying mechanisms of virus-triggered inflammatory responses are currently unknown. Here we report that SARS-CoV-2 Infection activates Caspase-8 to trigger cell Apoptosis and inflammatory cytokine processing in the lung epithelial cells. The processed inflammatory cytokines are released through the virus-induced Necroptosis pathway. Virus-induced Apoptosis, Necroptosis, and inflammation activation were also observed in the lung sections of SARS-CoV-2-infected HFH4-hACE2 transgenic mouse model, a valid model for studying SARS-CoV-2 pathogenesis. Furthermore, analysis of the postmortem lung sections of fatal COVID-19 patients revealed not only Apoptosis and Necroptosis but also massive inflammatory cell infiltration, necrotic cell debris, and pulmonary interstitial fibrosis, typical of immune pathogenesis in the lung. The SARS-CoV-2 Infection triggered a dual mode of cell death pathways and caspase-8-dependent inflammatory responses may lead to the lung damage in the COVID-19 patients. These discoveries might assist the development of therapeutic strategies to treat COVID-19.

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