Abstract
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.
Highlights
INTRODUCTION The outbreak of COVID19 caused by SARS-CoV-21,2 poses a great threat to global public health
SARS-CoV-2 infection activates the cGAS-STING pathway We recently reported that SARS-CoV-2 infection failed to induce rapid IFN-β production in cultured cells,[6] consistent with multiple inhibitory mechanisms against the RIG-I-like receptors (RLRs) pathway imposed by the virus
Our study revealed that host self-DNA, distinct from pathogen genetic molecules, can serve as a danger signal to trigger antiviral responses in SARS-CoV-2 infection
Summary
INTRODUCTION The outbreak of COVID19 caused by SARS-CoV-21,2 poses a great threat to global public health. Since innate immunity plays pivotal roles in both host defense and viral immunopathology, understanding the roles of innate immunity involved in SARS-CoV-2 infection is an important biomedical objective. Activation of the innate immune system upon viral infection is generally thought to be initiated by recognizing specific viral components, termed as pathogen-associated molecular patterns (PAMPs) that are recognized by host pattern recognition receptors (PRRs).[3] Viral genetic materials, such as genomic RNA, are detected by RIG-I-like receptors (RLRs), including RIG-I or MDA5, and the Toll-like receptors (TLRs). RLRs and cGAS stimulate adaptor molecules MAVS and STING, respectively, to activate downstream signaling pathways that eventually trigger the expression of antiviral or immunoregulatory cytokines, such as interferons (IFNs).[4] In addition to sensing viral components, the RLRs and cGAS pathways are reported to mediate sterile inflammation in the absence of infection induced by self-nucleic acids, such as in autoimmune disorders.[5] Whether host nucleic acids can mediate antiviral immunity is poorly understood
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