Modulation of type I interferon responses potently inhibits SARS-CoV-2 replication and inflammation in rhesus macaques
- PMID: 37506197
- PMCID: PMC10936760
- DOI: 10.1126/sciimmunol.adg0033
Modulation of type I interferon responses potently inhibits SARS-CoV-2 replication and inflammation in rhesus macaques
Abstract
Type I interferons (IFN-I) are critical mediators of innate control of viral infections but also drive the recruitment of inflammatory cells to sites of infection, a key feature of severe coronavirus disease 2019. Here, IFN-I signaling was modulated in rhesus macaques (RMs) before and during acute SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection using a mutated IFN-α2 (IFN-modulator; IFNmod), which has previously been shown to reduce the binding and signaling of endogenous IFN-I. IFNmod treatment in uninfected RMs was observed to induce a modest up-regulation of only antiviral IFN-stimulated genes (ISGs); however, in SARS-CoV-2-infected RMs, IFNmod reduced both antiviral and inflammatory ISGs. IFNmod treatment resulted in a potent reduction in SARS-CoV-2 viral loads both in vitro in Calu-3 cells and in vivo in bronchoalveolar lavage (BAL), upper airways, lung, and hilar lymph nodes of RMs. Furthermore, in SARS-CoV-2-infected RMs, IFNmod treatment potently reduced inflammatory cytokines, chemokines, and CD163+ MRC1- inflammatory macrophages in BAL and expression of Siglec-1 on circulating monocytes. In the lung, IFNmod also reduced pathogenesis and attenuated pathways of inflammasome activation and stress response during acute SARS-CoV-2 infection. Using an intervention targeting both IFN-α and IFN-β pathways, this study shows that, whereas early IFN-I restrains SARS-CoV-2 replication, uncontrolled IFN-I signaling critically contributes to SARS-CoV-2 inflammation and pathogenesis in the moderate disease model of RMs.
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Modulation of type I interferon responses potently inhibits SARS-CoV-2 replication and inflammation in rhesus macaques.bioRxiv [Preprint]. 2022 Oct 24:2022.10.21.512606. doi: 10.1101/2022.10.21.512606. bioRxiv. 2022. Update in: Sci Immunol. 2023 Jul 28;8(85):eadg0033. doi: 10.1126/sciimmunol.adg0033. PMID: 36324810 Free PMC article. Updated. Preprint.
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