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

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Title: The cGAS–STING pathway drives type I IFN immunopathology in COVID-19
Authors: 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, Andrea Ablasser
Source: Nature
Nature, vol. 603, no. 7899, pp. 145-151
Domizio, Jeremy Di; Gulen, Muhammet F; Saidoune, Fanny; Thacker, Vivek V; Yatim, Ahmad; Sharma, Kunal; Nass, Théo; Guenova, Emmanuella; Schaller, Martin; Conrad, Curdin; Goepfert, Christine; de Leval, Laurence; Garnier, Christophe von; Berezowska, Sabina; Dubois, Anaëlle; Gilliet, Michel; Ablasser, Andrea (2022). The cGAS-STING pathway drives type I IFN immunopathology in COVID-19. Nature, 603(7899), pp. 145-151. Springer Nature 10.1038/s41586-022-04421-w <http://dx.doi.org/10.1038/s41586-022-04421-w>
Publisher Information: Springer Science and Business Media LLC, 2022.
Publication Year: 2022
Subject Terms: 0301 basic medicine, DNA, Mitochondrial, Article, Mice, 03 medical and health sciences, Animals, Humans, 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, Immunity, Innate, Interferon Type I/immunology, Lung/immunology, Lung/metabolism, Lung/pathology, Lung/virology, Macrophages/immunology, Membrane Proteins/antagonists & inhibitors, Membrane Proteins/metabolism, 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, Lung, 630 Agriculture, SARS-CoV-2, Macrophages, COVID-19, Endothelial Cells, Membrane Proteins, Pneumonia, Nucleotidyltransferases, 3. Good health, Gene Expression Regulation, Interferon Type I, 570 Life sciences, biology, 590 Animals (Zoology)
Description: 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.
Document Type: Article
Other literature type
File Description: application/pdf
Language: English
ISSN: 1476-4687
0028-0836
DOI: 10.1038/s41586-022-04421-w
DOI: 10.48350/180918
Access URL: https://www.nature.com/articles/s41586-022-04421-w.pdf
https://pubmed.ncbi.nlm.nih.gov/35045565
https://serval.unil.ch/notice/serval:BIB_EB150385781D
http://nbn-resolving.org/urn/resolver.pl?urn=urn:nbn:ch:serval-BIB_EB150385781D5
https://serval.unil.ch/resource/serval:BIB_EB150385781D.P001/REF.pdf
https://boris.unibe.ch/180918/
Rights: CC BY
URL: http://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (http://creativecommons.org/licenses/by/4.0/) .
Accession Number: edsair.doi.dedup.....4a3db7ab2ba4412f5ae57a6972f38d81
Database: OpenAIRE
Description
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.
ISSN:14764687
00280836
DOI:10.1038/s41586-022-04421-w