Modulation of type I interferon responses potently inhibits SARS-CoV-2 replication and inflammation in rhesus macaques.

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.

Citation

Elise G Viox, Timothy N Hoang, Amit A Upadhyay, Rayhane Nchioua, Maximilian Hirschenberger, Zachary Strongin, Gregory K Tharp, Maria Pino, Kevin Nguyen, Justin L Harper, Matthew Gagne, Shir Marciano, Arun K Boddapati, Kathryn L Pellegrini, Arpan Pradhan, Jennifer Tisoncik-Go, Leanne S Whitmore, Kirti A Karunakaran, Melissa Roy, Shannon Kirejczyk, Elizabeth H Curran, Chelsea Wallace, Jennifer S Wood, Fawn Connor-Stroud, Emily A Voigt, Christopher M Monaco, David E Gordon, Sudhir P Kasturi, Rebecca D Levit, Michael Gale, Thomas H Vanderford, Guido Silvestri, Kathleen Busman-Sahay, Jacob D Estes, Monica Vaccari, Daniel C Douek, Konstantin M J Sparrer, R Paul Johnson, Frank Kirchhoff, Gideon Schreiber, Steven E Bosinger, Mirko Paiardini. Modulation of type I interferon responses potently inhibits SARS-CoV-2 replication and inflammation in rhesus macaques. Science immunology. 2023 Jul 28;8(85):eadg0033

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PMID: 37506197

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