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. [email protected].
  • 10. Global Health Institute, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland. [email protected].
  • # 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 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.