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

Domizio, Jeremy Di; Gulen, Muhammet F; Saidoune, Fanny; Thacker, Vivek V; Yatim, Ahmad; Sharma, Kunal; Nass, Théo; Guenova, Emmanuella; Schaller, Martin; Conrad, Curdin; Goepfert, Christine; de Leval, Laurence; Garnier, Christophe von; Berezowska, Sabina; Dubois, Anaëlle; Gilliet, Michel; Ablasser, Andrea (2022). The cGAS-STING pathway drives type I IFN immunopathology in COVID-19. Nature, 603(7899), pp. 145-151. Springer Nature 10.1038/s41586-022-04421-w

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COVID-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.

Item Type:

Journal Article (Original Article)


05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Animal Pathology
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)

UniBE Contributor:

Göpfert, Christine


500 Science > 570 Life sciences; biology
500 Science > 590 Animals (Zoology)
600 Technology > 630 Agriculture




Springer Nature




Katharina Gerber-Paizs

Date Deposited:

29 Mar 2023 10:32

Last Modified:

29 Mar 2023 23:28

Publisher DOI:


PubMed ID:





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