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

Nature. 2022 Mar;603(7899):145-151. doi: 10.1038/s41586-022-04421-w.

Jeremy Di Domizio ^# ¹, Muhammet F Gulen ^# ², Fanny Saidoune ^# ¹, Vivek V Thacker ^# ², Ahmad Yatim ^# ¹, Kunal Sharma ², Théo Nass ², Emmanuella Guenova ¹, Martin Schaller ³, Curdin Conrad ¹, Christine Goepfert ⁴ ⁵, Laurence de Leval ⁶, Christophe von Garnier ⁷, Sabina Berezowska ⁶, Anaëlle Dubois ⁸, Michel Gilliet ⁹, Andrea Ablasser ¹⁰

Affiliations

1 Department of Dermatology, CHUV University Hospital and University of Lausanne (UNIL), Lausanne, Switzerland.
2 Global Health Institute, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland.
3 University Department of Dermatology, Eberhard Karls University of Tübingen, Tübingen, Germany.
4 Institute of Animal Pathology, COMPATH, University of Bern, Bern, Switzerland.
5 Histology Core Facility, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland.
6 Institute of Pathology, CHUV University Hospital and University of Lausanne (UNIL), Lausanne, Switzerland.
7 Division of Pulmonology, CHUV University Hospital and University of Lausanne (UNIL), Lausanne, Switzerland.
8 Biological Electron Microscopy Facility, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland.
9 Department of Dermatology, CHUV University Hospital and University of Lausanne (UNIL), Lausanne, Switzerland. michel.gilliet@chuv.ch.
10 Global Health Institute, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland. andrea.ablasser@epfl.ch.
# Contributed equally.

PMID: 35045565 DOI: 10.1038/s41586-022-04421-w

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.

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