SARS-CoV-2 triggers inflammatory responses and cell death through caspase-8 activation
Open accessAbstract
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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Increased TNF and caspase 8 concentrations with minimal evidence of caspase 3-dependent apoptosis suggested a role for inflammatory-driven cell death pathways (e.g., necroptosis).
“Increased TNF and caspase 8 concentrations with minimal evidence of caspase 3–dependent apoptosis suggested a role for inflammatory-driven cell death pathways (e.g., necroptosis), as previously reported (39).”
From Lung epithelial and endothelial damage, loss of tissue repair, inhibition of fibrinolysis, and cellular senescence in fatal COVID-19 (2021) · cites this paper as [39]
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- Authors
- Li, S., Zhang, Y., Guan, Z., Li, H., Ye, M., Chen, X., Shen, J., Zhou, Y., Shi, Z.-L., Zhou, P., & Peng, K.
- Affiliations
- Chinese Academy of Sciences (CN)
- Wuhan No.1 Hospital (CN)
- Children's Hospital of Fudan University (CN)
- Huazhong University of Science and Technology (CN)
- Corresponding author
- Zhou, Peng
- Peng, Ke
- Venue
- Signal Transduction and Targeted Therapy
- Published
- 2020-10-09
- Volume
- 5
- Issue
- 1
- Pages
- 235-235
- ISSN
- 2059-3635 (ISSN-L)
- PMC
- PMC7545816
- OpenAlex
- W3092576617
- Cited by
- 365
- References
- 24
- Citations by year
- 2026: 12 · 2025: 34 · 2024: 54 · 2023: 74 · 2022: 81 · 2021: 108 · 2020: 2
- FWCI
- 8.68
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Signal Transduction and Targeted Therapy (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (31770188)
- Topics
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- SARS-CoV-2, COVID-19 pandemic, caspase-8, apoptosis, necroptosis, inflammatory cytokines, cytokine processing, lung epithelial cells, lung injury, interstitial pulmonary fibrosis, inflammatory cell infiltration, cell death pathways
- MeSH terms
- Betacoronavirus, Necroptosis, Cytokine Release Syndrome, COVID-19, SARS-CoV-2, Animals, Disease Models, Animal, Epithelial Cells, Gene Expression Regulation, Humans, Lung, Mice, Transgenic, Pneumonia, Viral, Pulmonary Fibrosis, Tumor Necrosis Factor-alpha, Interleukin-7, Interleukin-8, Apoptosis, Coronavirus Infections, Chemokine CCL5, Cell Line, Tumor, Mice, Caspase 8, Interleukin-1beta, Chemokine CXCL10, Pandemics
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