The global coronavirus disease 2019(COVID-19)pandemic is caused by severe acute respiratory syndrome coronavirus 2(SARSCoV-2),a positive-sense RNA virus.How the host immune system senses and responds to SARS-CoV-2 inf...The global coronavirus disease 2019(COVID-19)pandemic is caused by severe acute respiratory syndrome coronavirus 2(SARSCoV-2),a positive-sense RNA virus.How the host immune system senses and responds to SARS-CoV-2 infection remain largely unresolved.Here,we report that SARS-CoV-2 infection activates the innate immune response through the cytosolic DNA sensing cGAS-STING pathway.SARS-CoV-2 infection induces the cellular level of 2′3′-cGAMP associated with STING activation.cGAS recognizes chromatin DNA shuttled from the nucleus as a result of cell-to-cell fusion upon SARS-CoV-2 infection.We further demonstrate that the expression of spike protein from SARS-CoV-2 and ACE2 from host cells is sufficient to trigger cytoplasmic chromatin upon cell fusion.Furthermore,cytoplasmic chromatin-cGAS-STING pathway,but not MAVS-mediated viral RNA sensing pathway,contributes to interferon and pro-inflammatory gene expression upon cell fusion.Finally,we show that cGAS is required for host antiviral responses against SARS-CoV-2,and a STING-activating compound potently inhibits viral replication.Together,our study reported a previously unappreciated mechanism by which the host innate immune system responds to SARS-CoV-2 infection,mediated by cytoplasmic chromatin from the infected cells.Targeting the cytoplasmic chromatin-cGAS-STING pathway may offer novel therapeutic opportunities in treating COVID-19.In addition,these findings extend our knowledge in host defense against viral infection by showing that host cells’self-nucleic acids can be employed as a“danger signal”to alarm the immune system.展开更多
基金This work was supported by grants from National Key R&D Program of China(2020YFA0707600 to Z.Z.,2020YFA0707800 to W.Wei.)the National Natural Science Foundation of China(81930063,31870893,and 81971948 to J.W.,Z.Z.,and X.L.)+3 种基金the National Major Sciences&Technology Project for Control and Prevention of Major Infectious Diseases in China(2018ZX10301401 to Z.Z.and X.L.)the Beijing Municipal Science&Technology Commission(Z181100001318009)Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(2016-I2M-1-014,2016-I2M-1-005 to J.W.and X.L.)the Beijing Advanced Innovation Center for Genomics(ICG)at Peking University,and the Peking-Tsinghua Center for Life Sciences.
文摘The global coronavirus disease 2019(COVID-19)pandemic is caused by severe acute respiratory syndrome coronavirus 2(SARSCoV-2),a positive-sense RNA virus.How the host immune system senses and responds to SARS-CoV-2 infection remain largely unresolved.Here,we report that SARS-CoV-2 infection activates the innate immune response through the cytosolic DNA sensing cGAS-STING pathway.SARS-CoV-2 infection induces the cellular level of 2′3′-cGAMP associated with STING activation.cGAS recognizes chromatin DNA shuttled from the nucleus as a result of cell-to-cell fusion upon SARS-CoV-2 infection.We further demonstrate that the expression of spike protein from SARS-CoV-2 and ACE2 from host cells is sufficient to trigger cytoplasmic chromatin upon cell fusion.Furthermore,cytoplasmic chromatin-cGAS-STING pathway,but not MAVS-mediated viral RNA sensing pathway,contributes to interferon and pro-inflammatory gene expression upon cell fusion.Finally,we show that cGAS is required for host antiviral responses against SARS-CoV-2,and a STING-activating compound potently inhibits viral replication.Together,our study reported a previously unappreciated mechanism by which the host innate immune system responds to SARS-CoV-2 infection,mediated by cytoplasmic chromatin from the infected cells.Targeting the cytoplasmic chromatin-cGAS-STING pathway may offer novel therapeutic opportunities in treating COVID-19.In addition,these findings extend our knowledge in host defense against viral infection by showing that host cells’self-nucleic acids can be employed as a“danger signal”to alarm the immune system.
