Abstract
COVID-19, which is caused by infection with SARS-CoV-2, is characterized by lung pathology and extrapulmonary complications 1,2 . Type I interferons (IFNs) have an essential role in the pathogenesis of COVID-19 (refs 3-5 ). Although rapid induction of type I IFNs limits virus propagation, a sustained increase in the levels of type I IFNs in the late phase of the infection is associated with aberrant inflammation and poor clinical outcome 5-17 . Here we show that the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which controls immunity to cytosolic DNA, is a critical driver of aberrant type I IFN responses in COVID-19 (ref. 18 ). Profiling COVID-19 skin manifestations, we uncover a STING-dependent type I IFN signature that is primarily mediated by macrophages adjacent to areas of endothelial cell damage. Moreover, cGAS-STING activity was detected in lung samples from patients with COVID-19 with prominent tissue destruction, and was associated with type I IFN responses. A lung-on-chip model revealed that, in addition to macrophages, infection with SARS-CoV-2 activates cGAS-STING signalling in endothelial cells through mitochondrial DNA release, which leads to cell death and type I IFN production. In mice, pharmacological inhibition of STING reduces severe lung inflammation induced by SARS-CoV-2 and improves disease outcome. Collectively, our study establishes a mechanistic basis of pathological type I IFN responses in COVID-19 and reveals a principle for the development of host-directed therapeutics.
【초록키워드】 COVID-19, SARS-CoV-2, Inflammation, Macrophage, Pathogenesis, macrophages, Immunity, Infection, interferons, interferon, lung, outcome, Clinical outcome, DNA, mice, endothelial cells, response, cGAS, Control, pathway, Complication, Manifestations, type I interferons, type I IFNs, mitochondrial DNA, cell death, disease, Critical, IFNs, STING, Lung pathology, Endothelial cell, Lung inflammation, Profiling, Type I IFN, mitochondrial, cyclic GMP, Rapid induction, tissue, principle, severe lung inflammation, pathogenesis of COVID-19, late phase, ChIP, pharmacological, type I IFN responses, endothelial cell damage, responses, limit, virus propagation, IMPROVE, caused, addition, characterized, increase in, activate, reduce, reveal, Type, sustained, cytosolic, infection with SARS-CoV-2, interferons (IFNs, patients with COVID-19, 【제목키워드】 COVID-19, immunopathology, pathway, Type I IFN,