tetano
Editor, Senior Moderator
Sci Immunol
. 2023 Jul 28;8(85):eadg0033.
doi: 10.1126/sciimmunol.adg0033. Epub 2023 Jul 28. Modulation of type I interferon responses potently inhibits SARS-CoV-2 replication and inflammation in rhesus macaques
Elise G Viox[SUP] 1 [/SUP], Timothy N Hoang[SUP] 1 [/SUP], Amit A Upadhyay[SUP] 1 [/SUP], Rayhane Nchioua[SUP] 2 [/SUP], Maximilian Hirschenberger[SUP] 2 [/SUP], Zachary Strongin[SUP] 1 [/SUP], Gregory K Tharp[SUP] 3 [/SUP], Maria Pino[SUP] 1 [/SUP], Kevin Nguyen[SUP] 1 [/SUP], Justin L Harper[SUP] 1 [/SUP], Matthew Gagne[SUP] 4 [/SUP], Shir Marciano[SUP] 5 [/SUP], Arun K Boddapati[SUP] 3 [/SUP], Kathryn L Pellegrini[SUP] 3 [/SUP], Arpan Pradhan[SUP] 1 [/SUP], Jennifer Tisoncik-Go[SUP] 6 [/SUP], Leanne S Whitmore[SUP] 6 [/SUP], Kirti A Karunakaran[SUP] 1 [/SUP], Melissa Roy[SUP] 7 [/SUP], Shannon Kirejczyk[SUP] 8 [/SUP], Elizabeth H Curran[SUP] 7 [/SUP], Chelsea Wallace[SUP] 9 [/SUP], Jennifer S Wood[SUP] 9 [/SUP], Fawn Connor-Stroud[SUP] 9 [/SUP], Emily A Voigt[SUP] 10 [/SUP], Christopher M Monaco[SUP] 11 [/SUP], David E Gordon[SUP] 11 [/SUP], Sudhir P Kasturi[SUP] 1 11 [/SUP], Rebecca D Levit[SUP] 12 [/SUP], Michael Gale Jr[SUP] 6 [/SUP], Thomas H Vanderford[SUP] 1 [/SUP], Guido Silvestri[SUP] 1 11 [/SUP], Kathleen Busman-Sahay[SUP] 13 [/SUP], Jacob D Estes[SUP] 13 14 15 16 [/SUP], Monica Vaccari[SUP] 17 18 [/SUP], Daniel C Douek[SUP] 4 [/SUP], Konstantin M J Sparrer[SUP] 2 [/SUP], R Paul Johnson[SUP] 1 19 [/SUP], Frank Kirchhoff[SUP] 2 [/SUP], Gideon Schreiber[SUP] 5 [/SUP], Steven E Bosinger[SUP] 1 3 11 [/SUP], Mirko Paiardini[SUP] 1 11 [/SUP]
Affiliations
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[SUP]+[/SUP] MRC1[SUP]-[/SUP] 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.
. 2023 Jul 28;8(85):eadg0033.
doi: 10.1126/sciimmunol.adg0033. Epub 2023 Jul 28. Modulation of type I interferon responses potently inhibits SARS-CoV-2 replication and inflammation in rhesus macaques
Elise G Viox[SUP] 1 [/SUP], Timothy N Hoang[SUP] 1 [/SUP], Amit A Upadhyay[SUP] 1 [/SUP], Rayhane Nchioua[SUP] 2 [/SUP], Maximilian Hirschenberger[SUP] 2 [/SUP], Zachary Strongin[SUP] 1 [/SUP], Gregory K Tharp[SUP] 3 [/SUP], Maria Pino[SUP] 1 [/SUP], Kevin Nguyen[SUP] 1 [/SUP], Justin L Harper[SUP] 1 [/SUP], Matthew Gagne[SUP] 4 [/SUP], Shir Marciano[SUP] 5 [/SUP], Arun K Boddapati[SUP] 3 [/SUP], Kathryn L Pellegrini[SUP] 3 [/SUP], Arpan Pradhan[SUP] 1 [/SUP], Jennifer Tisoncik-Go[SUP] 6 [/SUP], Leanne S Whitmore[SUP] 6 [/SUP], Kirti A Karunakaran[SUP] 1 [/SUP], Melissa Roy[SUP] 7 [/SUP], Shannon Kirejczyk[SUP] 8 [/SUP], Elizabeth H Curran[SUP] 7 [/SUP], Chelsea Wallace[SUP] 9 [/SUP], Jennifer S Wood[SUP] 9 [/SUP], Fawn Connor-Stroud[SUP] 9 [/SUP], Emily A Voigt[SUP] 10 [/SUP], Christopher M Monaco[SUP] 11 [/SUP], David E Gordon[SUP] 11 [/SUP], Sudhir P Kasturi[SUP] 1 11 [/SUP], Rebecca D Levit[SUP] 12 [/SUP], Michael Gale Jr[SUP] 6 [/SUP], Thomas H Vanderford[SUP] 1 [/SUP], Guido Silvestri[SUP] 1 11 [/SUP], Kathleen Busman-Sahay[SUP] 13 [/SUP], Jacob D Estes[SUP] 13 14 15 16 [/SUP], Monica Vaccari[SUP] 17 18 [/SUP], Daniel C Douek[SUP] 4 [/SUP], Konstantin M J Sparrer[SUP] 2 [/SUP], R Paul Johnson[SUP] 1 19 [/SUP], Frank Kirchhoff[SUP] 2 [/SUP], Gideon Schreiber[SUP] 5 [/SUP], Steven E Bosinger[SUP] 1 3 11 [/SUP], Mirko Paiardini[SUP] 1 11 [/SUP]
Affiliations
- PMID: 37506197
- DOI: 10.1126/sciimmunol.adg0033
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[SUP]+[/SUP] MRC1[SUP]-[/SUP] 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.