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

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Abstract

Coronavirus disease 2019 (COVID-19), caused by infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is characterized by significant lung pathology and extrapulmonary complications^1,2. Type I interferons (IFNs) play an essential role in the pathogenesis of COVID-19^3–5. While rapid induction of type I IFNs limits virus propagation, sustained elevation of type I IFNs in the late phase of the infection is associated with aberrant inflammation and poor clinical outcome^5–17. Here, we identify the cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING)-pathway, which controls immunity to cytosolic DNA, as a critical driver of aberrant type I IFN responses in COVID-19¹⁸. Profiling COVID-19 skin manifestations, we uncover a STING-dependent type I IFN signature primarily mediated by macrophages adjacent to areas of endothelial cell damage. Moreover, cGAS-STING activity was detected in lung samples of COVID-19 patients with prominent tissue destruction and associated with type I IFN responses. A lung-on-chip model revealed that, in addition to macrophages, SARS-CoV-2 infection activates cGAS-STING signalling in endothelial cells through mitochondrial DNA release, leading 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 novel principle for the development of host-directed therapeutics.

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Author notes

1. These authors contributed equally: Jeremy Di Domizio, Muhammet F. Gulen, Fanny Saidoune, Vivek V. Thacker, Ahmad Yatim

2. These authors jointly supervised this work: Michel Gilliet, Andrea Ablasser

Affiliations

1. Department of Dermatology, CHUV University Hospital and University of Lausanne (UNIL), Lausanne, Switzerland

   Jeremy Di Domizio, Fanny Saidoune, Ahmad Yatim, Emmanuella Guenova, Curdin Conrad & Michel Gilliet

2. Global Health Institute, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland

   Muhammet F. Gulen, Vivek V. Thacker, Kunal Sharma, Théo Nass & Andrea Ablasser

3. University Department of Dermatology, Eberhard Karls University of Tübingen, Tübingen, Germany

   Martin Schaller

4. Institute of Animal Pathology, COMPATH, University of Bern, Bern, Switzerland

   Christine Goepfert

5. Histology Core Facility, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland

   Christine Goepfert

6. Institute of Pathology, CHUV University Hospital and University of Lausanne (UNIL), Lausanne, Switzerland

   Laurence De Leval & Sabina Berezowska

7. Division of Pulmonology, CHUV University Hospital and University of Lausanne (UNIL), Lausanne, Switzerland

   Christophe von Garnier

8. Biological Electron Microscopy Facility, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland

   Anaëlle Dubois

Authors

1. Jeremy Di Domizio
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2. Muhammet F. Gulen
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3. Fanny Saidoune
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4. Vivek V. Thacker
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5. Ahmad Yatim
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6. Kunal Sharma
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7. Théo Nass
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8. Emmanuella Guenova
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9. Martin Schaller
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10. Curdin Conrad
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11. Christine Goepfert
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12. Laurence De Leval
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13. Christophe von Garnier
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14. Sabina Berezowska
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15. Anaëlle Dubois
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16. Michel Gilliet
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17. Andrea Ablasser
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Corresponding authors

Correspondence to Michel Gilliet or Andrea Ablasser.

Supplementary information

Supplementary Figure 1

This file contains full scans for all western blots and the in-gel fluorescence images, in Supplementary Fig. 1.

Reporting Summary

Supplementary Table 1

A list of antibodies used in this study.

Supplementary Table 2

A list of qRT-PCR primers and shRNA sequences in this study.

Supplementary Table 3

Data for pairwise comparison (Limma analysis) and timecourse analysis of the proteomics data in this study.

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Di Domizio, J., Gulen, M.F., Saidoune, F. et al. The cGAS-STING pathway drives type I IFN immunopathology in COVID-19. Nature (2022). https://ift.tt/3nEsd0W

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• Received: 18 June 2021

• Accepted: 13 January 2022

• Published: 19 January 2022

• DOI: https://ift.tt/3nEsd0W

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