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.
【저자키워드】 Inflammation, Infectious diseases, 【초록키워드】 COVID-19, coronavirus disease, SARS-CoV-2, Apoptosis, coronavirus, Pathogenesis, SARS-COV-2 infection, Infection, lung, Respiratory illness, immune, clinical manifestations, Patient, pathway, SARS-CoV-2 pathogenesis, mechanism, therapeutic strategy, critically ill patients, Inflammatory cytokine, Lung epithelial cells, COVID-19 patients, infiltration, Inflammatory response, Analysis, Inflammatory cytokine storm, necroptosis, lung damage, caspase-8, acute respiratory syndrome, Activation, necrotic, multi-organ failure, treat, pulmonary interstitial fibrosis, fatal COVID-19, Cell, Transgenic mouse, triggered, activate, released, processed, assist, cell death pathway, cell debris, HFH4-hACE2, massive inflammatory, 【제목키워드】 SARS-CoV-2, cell death, Inflammatory response, Trigger, caspase-8, Activation,