The global coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-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.
【저자키워드】 Infectious diseases, Innate immunity, 【초록키워드】 COVID-19, coronavirus disease, SARS-CoV-2, viral infection, Coronavirus disease 2019, ACE2, coronavirus, pandemic, innate immune response, knowledge, SARS-COV-2 infection, interferon, immune system, severe acute respiratory syndrome Coronavirus, Spike protein, innate immune system, DNA, Viral, nucleic acids, viral replication, therapeutic, Cell fusion, cGAS, pathway, Viral RNA, RNA virus, respiratory, expression, mechanism, STING, cellular, host defense, MAVS, Trigger, host cells, host cell, acute respiratory syndrome, Activation, acute respiratory syndrome coronavirus, acute respiratory syndrome coronavirus 2, infected cells, host antiviral response, host immune system, positive-sense RNA virus, treating COVID-19, nucleus, Defense, chromatin, targeting, offer, host antiviral responses, pro-inflammatory gene expression, Host, Cell, caused, reported, addition, inhibit, required, contribute, recognize, cytoplasmic, induce, activate, respond, cytosolic, 【제목키워드】 chromatin, cytoplasmic, activate,