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

2023; American Association for the Advancement of Science; Volume: 8; Issue: 85 Linguagem: Inglês

10.1126/sciimmunol.adg0033

2470-9468

Elise G. Viox, Timothy N. Hoang, Amit A. Upadhyay, Rayhane Nchioua, Maximilian Hirschenberger, Zachary Strongin, Gregory K. Tharp, María Pino, Kevin Nguyen, Justin Harper, Matthew Gagné, Shir Marciano, Arun K. Boddapati, Kathryn L. Pellegrini, Arpan Pradhan, Jennifer Tisoncik-Go, Leanne S. Whitmore, Kirti A. Karunakaran, Mélissa Roy, Shannon G. M. Kirejczyk, Elizabeth Curran, Chelsea Wallace, Jennifer Wood, Fawn Connor‐Stroud, Emily A. Voigt, Christopher M. Monaco, David E. Gordon, Sudhir Pai 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,

interferon and immune responses

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.