5 Indeed, virus-induced cytokine storm and sepsis has claimed the death of 28% of fatal COVID-19 cases. 3, 4 Inflammatory responses from infected cells may further induce infiltration of immune cells into the lung causing overproduction of pro-inflammatory cytokines resulting in severe lung damage and multi-organ dysfunction. 2 Elevated levels of serum interleukin (IL)-6 and other inflammatory cytokines correlate with respiratory failure, ARDS, and adverse clinical outcomes. Severe disease manifested by fever and pneumonia, leading to acute respiratory distress syndrome (ARDS), has been described in up to 20% of COVID-19 cases. 1 As of 24 July 2020, SARS-CoV-2 had infected over 15 million people worldwide and had claimed the death of over 630,000 people. Virus infection causes severe respiratory illness in the patients, called the coronavirus disease 2019 (COVID-19). Since its emergence in December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic transmission in the world. These discoveries might assist the development of therapeutic strategies to treat COVID-19. 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. 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. 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.
The processed inflammatory cytokines are released through the virus-induced necroptosis pathway. Here we report that SARS-CoV-2 infection activates caspase-8 to trigger cell apoptosis and inflammatory cytokine processing in the lung epithelial cells. 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. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to respiratory illness and multi-organ failure in critically ill patients.
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