Domizio, Jeremy DiJeremy DiDomizioGulen, Muhammet FMuhammet FGulenSaidoune, FannyFannySaidouneThacker, Vivek VVivek VThackerYatim, AhmadAhmadYatimSharma, KunalKunalSharmaNass, ThéoThéoNassGuenova, EmmanuellaEmmanuellaGuenovaSchaller, MartinMartinSchallerConrad, CurdinCurdinConradGöpfert, ChristineChristineGöpfertde Leval, LaurenceLaurencede LevalGarnier, Christophe vonChristophe vonGarnierBerezowska, SabinaSabinaBerezowskaDubois, AnaëlleAnaëlleDuboisGilliet, MichelMichelGillietAblasser, AndreaAndreaAblasser2024-10-252024-10-252022-03https://boris-portal.unibe.ch/handle/20.500.12422/165819COVID-19, which is caused by infection with SARS-CoV-2, is characterized by lung pathology and extrapulmonary complications1,2. 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 outcome5-17. 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.en500 - Science::570 - Life sciences; biology500 - Science::590 - Animals (Zoology)600 - Technology::630 - Agriculturearticle10.48350/1809183504556510.1038/s41586-022-04421-w