tetano
Editor, Senior Moderator
Nature
. 2022 Jan 19.
doi: 10.1038/s41586-022-04421-w. Online ahead of print.
The cGAS-STING pathway drives type I IFN immunopathology in COVID-19
Jeremy Di Domizio[SUP] #[/SUP][SUP] 1 [/SUP], Muhammet F Gulen[SUP] #[/SUP][SUP] 2 [/SUP], Fanny Saidoune[SUP] #[/SUP][SUP] 1 [/SUP], Vivek V Thacker[SUP] #[/SUP][SUP] 2 [/SUP], Ahmad Yatim[SUP] #[/SUP][SUP] 1 [/SUP], Kunal Sharma[SUP] 2 [/SUP], Théo Nass[SUP] 2 [/SUP], Emmanuella Guenova[SUP] 1 [/SUP], Martin Schaller[SUP] 3 [/SUP], Curdin Conrad[SUP] 1 [/SUP], Christine Goepfert[SUP] 4 5 [/SUP], Laurence De Leval[SUP] 6 [/SUP], Christophe von Garnier[SUP] 7 [/SUP], Sabina Berezowska[SUP] 6 [/SUP], Anaëlle Dubois[SUP] 8 [/SUP], Michel Gilliet[SUP] 9 [/SUP], Andrea Ablasser[SUP] 10 [/SUP]
Affiliations
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[SUP]1,2[/SUP]. Type I interferons (IFNs) play an essential role in the pathogenesis of COVID-19[SUP]3-5[/SUP]. 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[SUP]5-17[/SUP]. 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-19[SUP]18[/SUP]. 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.
. 2022 Jan 19.
doi: 10.1038/s41586-022-04421-w. Online ahead of print.
The cGAS-STING pathway drives type I IFN immunopathology in COVID-19
Jeremy Di Domizio[SUP] #[/SUP][SUP] 1 [/SUP], Muhammet F Gulen[SUP] #[/SUP][SUP] 2 [/SUP], Fanny Saidoune[SUP] #[/SUP][SUP] 1 [/SUP], Vivek V Thacker[SUP] #[/SUP][SUP] 2 [/SUP], Ahmad Yatim[SUP] #[/SUP][SUP] 1 [/SUP], Kunal Sharma[SUP] 2 [/SUP], Théo Nass[SUP] 2 [/SUP], Emmanuella Guenova[SUP] 1 [/SUP], Martin Schaller[SUP] 3 [/SUP], Curdin Conrad[SUP] 1 [/SUP], Christine Goepfert[SUP] 4 5 [/SUP], Laurence De Leval[SUP] 6 [/SUP], Christophe von Garnier[SUP] 7 [/SUP], Sabina Berezowska[SUP] 6 [/SUP], Anaëlle Dubois[SUP] 8 [/SUP], Michel Gilliet[SUP] 9 [/SUP], Andrea Ablasser[SUP] 10 [/SUP]
Affiliations
- PMID: 35045565
- DOI: 10.1038/s41586-022-04421-w
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[SUP]1,2[/SUP]. Type I interferons (IFNs) play an essential role in the pathogenesis of COVID-19[SUP]3-5[/SUP]. 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[SUP]5-17[/SUP]. 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-19[SUP]18[/SUP]. 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.