TY - JOUR
T1 - Modulation of type I interferon responses potently inhibits SARS-CoV-2 replication and inflammation in rhesus macaques
AU - Viox, Elise G.
AU - Hoang, Timothy N.
AU - Upadhyay, Amit A.
AU - Nchioua, Rayhane
AU - Hirschenberger, Maximilian
AU - Strongin, Zachary
AU - Tharp, Gregory K.
AU - Pino, Maria
AU - Nguyen, Kevin
AU - Harper, Justin L.
AU - Gagne, Matthew
AU - Marciano, Shir
AU - Boddapati, Arun K.
AU - Pellegrini, Kathryn L.
AU - Pradhan, Arpan
AU - Tisoncik-Go, Jennifer
AU - Whitmore, Leanne S.
AU - Karunakaran, Kirti A.
AU - Roy, Melissa
AU - Kirejczyk, Shannon
AU - Curran, Elizabeth H.
AU - Wallace, Chelsea
AU - Wood, Jennifer S.
AU - Connor-Stroud, Fawn
AU - Voigt, Emily A.
AU - Monaco, Christopher M.
AU - Gordon, David E.
AU - Kasturi, Sudhir P.
AU - Levit, Rebecca D.
AU - Gale, Michael
AU - Vanderford, Thomas H.
AU - Silvestri, Guido
AU - Busman-Sahay, Kathleen
AU - Estes, Jacob D.
AU - Vaccari, Monica
AU - Douek, Daniel C.
AU - Sparrer, Konstantin M.J.
AU - Johnson, R. Paul
AU - Kirchhoff, Frank
AU - Schreiber, Gideon
AU - Bosinger, Steven E.
AU - Paiardini, Mirko
N1 - Publisher Copyright:
© 2023 The Authors.
PY - 2023/7
Y1 - 2023/7
N2 - 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.
AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=85165942131&partnerID=8YFLogxK
U2 - 10.1126/sciimmunol.adg0033
DO - 10.1126/sciimmunol.adg0033
M3 - Article
C2 - 37506197
AN - SCOPUS:85165942131
SN - 2470-9468
VL - 8
JO - Science Immunology
JF - Science Immunology
IS - 85
M1 - adg0033
ER -