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

Jeremy Di Domizio, Muhammet F. Gulen, Fanny Saidoune, Vivek V. Thacker, Ahmad Yatim, Kunal Sharma, Théo Nass, Emmanuella Guenova, Martin Schaller, Curdin Conrad, Christine Goepfert, Laurence de Leval, Christophe von Garnier, Sabina Berezowska, Anaëlle Dubois, Michel Gilliet () and Andrea Ablasser ()
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Jeremy Di Domizio: CHUV University Hospital and University of Lausanne (UNIL)
Muhammet F. Gulen: Swiss Federal Institute of Technology Lausanne (EPFL)
Fanny Saidoune: CHUV University Hospital and University of Lausanne (UNIL)
Vivek V. Thacker: Swiss Federal Institute of Technology Lausanne (EPFL)
Ahmad Yatim: CHUV University Hospital and University of Lausanne (UNIL)
Kunal Sharma: Swiss Federal Institute of Technology Lausanne (EPFL)
Théo Nass: Swiss Federal Institute of Technology Lausanne (EPFL)
Emmanuella Guenova: CHUV University Hospital and University of Lausanne (UNIL)
Martin Schaller: University Department of Dermatology, Eberhard Karls University of Tübingen
Curdin Conrad: CHUV University Hospital and University of Lausanne (UNIL)
Christine Goepfert: University of Bern
Laurence de Leval: CHUV University Hospital and University of Lausanne (UNIL)
Christophe von Garnier: CHUV University Hospital and University of Lausanne (UNIL)
Sabina Berezowska: CHUV University Hospital and University of Lausanne (UNIL)
Anaëlle Dubois: Swiss Federal Institute of Technology Lausanne (EPFL)
Michel Gilliet: CHUV University Hospital and University of Lausanne (UNIL)
Andrea Ablasser: Swiss Federal Institute of Technology Lausanne (EPFL)

Nature, 2022, vol. 603, issue 7899, 145-151

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41586-022-04421-w

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