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.
Highlights
Consistent with the specific expression of macrophage signature genes, the numbers of CD163+ macrophages were higher in COVID-19 skin lesions relative to CLE (Fig. 1b, Extended Data Fig. 3a)
Plasmacytoid dendritic cells—but not macrophages—were enriched in CLE samples, whereas the numbers of neutrophils and T cells were similar in the two conditions (Fig. 1b, Extended Data Fig. 3a)
Further examination of macrophages revealed that these cells consistently showed a robust IFNβ response across all samples (Fig. 1c, d, f)
Summary
Time (dpi) at 2 dpi), related to data from f–h. f, Left, representative H&E images of lungs from vehicle- and H-151-treated mice. Cell death was efficiently blocked by treatment with H-151 at 6 dpi, but not at 3 dpi (Extended Data Fig. 9a) These findings show that STING is a critical contributor to SARS-CoV-2-induced lung pathology. At 3 dpi there was no appreciable difference in cytokine levels in the lungs between the two treatment groups (Extended Data Fig. 9b) These data show that STING has a unique and critical function in eliciting type I IFN and inflammatory responses in the late phase of infection, which coincides with excessive tissue damage, but not with the peak of viral replication[32]. Mice that received H-151 at 2 dpi showed reduced pathology and decreased levels of type I IFNs and other cytokines in the lungs compared to those that were treated with vehicle only, whereas viral loads were similar between the two groups (Fig. 4f, Extended Data Fig. 10a, b). Together with the data above, these results corroborate the select role of STING in promoting detrimental inflammation during the late (or later) stages of the infection and highlight the therapeutic efficacy of STING inhibition, whether in a prophylactic or a therapeutic setting
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