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Type I interferon autoantibody footprints reveal neutralizing mechanisms and allow inhibitory decoy design

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Názov: Type I interferon autoantibody footprints reveal neutralizing mechanisms and allow inhibitory decoy design
Autori: Groen, Kevin, Kuratli, Roger, Enkelmann, Jannik, Fernbach, Sonja, Wendel-Garcia, Pedro D, Staiger, Willy I, Lejeune, Marylène, Sauras-Colón, Esther, Roche-Campo, Ferran, Filippidis, Paraskevas, Rauch, Andri, Trkola, Alexandra, Günthard, Huldrych F, Kouyos, Roger D, Brugger, Silvio D, Hale, Benjamin G, Swiss HIV Cohort Study
Prispievatelia: Bernasconi, Enos, Calmy, Alexandra, Kaiser, Laurent, Keiser, Olivia, Martinez De Tejada Weber, Begona, Yerly Ferrillo, Sabine
Zdroj: ISSN: 0022-1007 ; The journal of experimental medicine, vol. 222, no. 6 (2025) e20242039.
Rok vydania: 2025
Zbierka: Université de Genève: Archive ouverte UNIGE
Predmety: info:eu-repo/classification/ddc/613, info:eu-repo/classification/ddc/616, info:eu-repo/classification/ddc/618, Humans, Autoantibodies / immunology, Autoantibodies / blood, Antibodies, Neutralizing / immunology, Interferon Type I / immunology, COVID-19 / immunology, Receptor, Interferon alpha-beta / immunology, Interferon alpha-beta / metabolism, SARS-CoV-2 / immunology, HIV-1 / immunology, HIV Infections / immunology, HEK293 Cells
Popis: Autoantibodies neutralizing type I interferons (IFN-Is; IFNα or IFNω) exacerbate severe viral disease, but specific treatments are unavailable. With footprint profiling, we delineate two dominant IFN-I faces commonly recognized by neutralizing IFN-I autoantibody-containing plasmas from aged individuals with HIV-1 and from individuals with severe COVID-19. These faces overlap with IFN-I regions independently essential for engaging the IFNAR1/IFNAR2 heterodimer, and neutralizing plasmas efficiently block the interaction of IFN-I with both receptor subunits in vitro. In contrast, non-neutralizing autoantibody-containing plasmas limit the interaction of IFN-I with only one receptor subunit and display relatively low IFN-I-binding avidities, thus likely hindering neutralizing function. Iterative engineering of signaling-inert mutant IFN-Is (simIFN-Is) retaining dominant autoantibody targets created potent decoys that prevent IFN-I neutralization by autoantibody-containing plasmas and that restore IFN-I-mediated antiviral activity. Additionally, microparticle-coupled simIFN-Is were effective at depleting IFN-I autoantibodies from plasmas, leaving antiviral antibodies unaffected. Our study reveals mechanisms of action for IFN-I autoantibodies and demonstrates a proof-of-concept strategy to alleviate pathogenic effects.
Druh dokumentu: article in journal/newspaper
Jazyk: English
Relation: info:eu-repo/semantics/altIdentifier/pmid/40111224; unige:188924
Dostupnosť: https://archive-ouverte.unige.ch/unige:188924
Rights: info:eu-repo/semantics/openAccess
Prístupové číslo: edsbas.56EDBA3
Databáza: BASE
Popis
Abstrakt:Autoantibodies neutralizing type I interferons (IFN-Is; IFNα or IFNω) exacerbate severe viral disease, but specific treatments are unavailable. With footprint profiling, we delineate two dominant IFN-I faces commonly recognized by neutralizing IFN-I autoantibody-containing plasmas from aged individuals with HIV-1 and from individuals with severe COVID-19. These faces overlap with IFN-I regions independently essential for engaging the IFNAR1/IFNAR2 heterodimer, and neutralizing plasmas efficiently block the interaction of IFN-I with both receptor subunits in vitro. In contrast, non-neutralizing autoantibody-containing plasmas limit the interaction of IFN-I with only one receptor subunit and display relatively low IFN-I-binding avidities, thus likely hindering neutralizing function. Iterative engineering of signaling-inert mutant IFN-Is (simIFN-Is) retaining dominant autoantibody targets created potent decoys that prevent IFN-I neutralization by autoantibody-containing plasmas and that restore IFN-I-mediated antiviral activity. Additionally, microparticle-coupled simIFN-Is were effective at depleting IFN-I autoantibodies from plasmas, leaving antiviral antibodies unaffected. Our study reveals mechanisms of action for IFN-I autoantibodies and demonstrates a proof-of-concept strategy to alleviate pathogenic effects.