The cGAS-STING pathway drives type I IFN immunopathology in COVID-19

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. The cGAS-STING pathway has a central role in the pathogenesis of severe COVID-19 by driving the increase in type I interferons that occurs in the later stages of SARS-CoV-2 infection.

Automated summary

This study reveals the mechanism behind aberrant type I interferon responses in COVID-19 through the cGAS-STING pathway and demonstrates its importance in severe cases. By using animal and lung-on-chip models, the study provides insights into host-directed therapeutic strategies for COVID-19.