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. Epub 2022 Jan 19.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COVID-19 / immunology*
  • COVID-19 / metabolism
  • COVID-19 / pathology*
  • COVID-19 / virology
  • Cells, Cultured
  • DNA, Mitochondrial / metabolism
  • Disease Models, Animal
  • Disease Progression
  • Endothelial Cells / pathology
  • Female
  • Gene Expression Regulation / immunology
  • Humans
  • Immunity, Innate
  • Interferon Type I / immunology*
  • Lung / immunology
  • Lung / metabolism
  • Lung / pathology
  • Lung / virology
  • Macrophages / immunology
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Nucleotidyltransferases / metabolism*
  • Pneumonia / immunology
  • Pneumonia / metabolism
  • Pneumonia / pathology
  • Pneumonia / virology
  • SARS-CoV-2 / immunology*
  • SARS-CoV-2 / pathogenicity
  • Signal Transduction
  • Skin / immunology
  • Skin / metabolism
  • Skin / pathology


  • DNA, Mitochondrial
  • Interferon Type I
  • Membrane Proteins
  • STING1 protein, human
  • Sting1 protein, mouse
  • Nucleotidyltransferases
  • cGAS protein, human