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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / immunology*
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Betacoronavirus / pathogenicity*
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COVID-19
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Caspase 8 / genetics
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Caspase 8 / immunology*
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Cell Line, Tumor
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Chemokine CCL5 / genetics
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Chemokine CCL5 / immunology
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Chemokine CXCL10 / genetics
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Chemokine CXCL10 / immunology
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Coronavirus Infections / genetics
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Coronavirus Infections / immunology*
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Coronavirus Infections / pathology
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Coronavirus Infections / virology
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Cytokine Release Syndrome / genetics
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Cytokine Release Syndrome / immunology*
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Cytokine Release Syndrome / pathology
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Cytokine Release Syndrome / virology
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Disease Models, Animal
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Epithelial Cells / immunology
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Epithelial Cells / pathology
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Epithelial Cells / virology
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Gene Expression Regulation
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Humans
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Interleukin-1beta / genetics
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Interleukin-1beta / immunology
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Interleukin-7 / genetics
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Interleukin-7 / immunology
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Interleukin-8 / genetics
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Interleukin-8 / immunology
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Lung / immunology
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Lung / pathology
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Lung / virology
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Mice
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Mice, Transgenic
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Necroptosis / immunology*
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Pandemics
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Pneumonia, Viral / genetics
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Pneumonia, Viral / immunology*
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Pneumonia, Viral / pathology
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Pneumonia, Viral / virology
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Pulmonary Fibrosis / genetics
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Pulmonary Fibrosis / immunology*
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Pulmonary Fibrosis / pathology
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Pulmonary Fibrosis / virology
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SARS-CoV-2
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / immunology
Substances
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CCL5 protein, human
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CXCL10 protein, human
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CXCL8 protein, human
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Chemokine CCL5
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Chemokine CXCL10
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IL1B protein, human
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IL7 protein, human
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Interleukin-1beta
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Interleukin-7
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Interleukin-8
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Tumor Necrosis Factor-alpha
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CASP8 protein, human
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Caspase 8