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 ...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.展开更多
基金supported by the National Science and Technology Major Project(number 2018ZX10101004001005)the National Key R&D Program of China(2018YFA0507201)+4 种基金the National Natural Science Foundation of China(numbers 31770188 and 31900144)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB29010204)the Hundred Talents Program of Chinese Academy of Sciences(to K.P.)the Special major program of Wuhan Institute of Virology(number WIV-135-TP1),the State Key Laboratory of Virology open projects(number 2017IOV003)the Advanced Customer Cultivation Project of Wuhan National Biosafety Laboratory Chinese Academy of Sciences(number 2018ACCPMS01).
文摘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.
