In:
Nature, Springer Science and Business Media LLC, Vol. 603, No. 7899 ( 2022-03-03), p. 145-151
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.
Type of Medium:
Online Resource
ISSN:
0028-0836
,
1476-4687
DOI:
10.1038/s41586-022-04421-w
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2022
detail.hit.zdb_id:
120714-3
detail.hit.zdb_id:
1413423-8
SSG:
11
Permalink
