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

• DOI: 10.1084/jem.20242039
• Publication Date: 2025-03-20T13:39:45Z
• Authors: Kevin Groen; Roger Kuratli; Jannik Enkelmann; Sonja Fernbach; Pedro D. Wendel-G...; Willy I. Staiger; Marylène Lejeune; Esther Sauras-Colón; Ferran Roche-Campo; Paraskevas Filipp...; Andri Rauch; ; Irene A. Abela; Karoline Aebi-Popp; Alexia Anagnostop...; Manuel Battegay; Enos Bernasconi; Dominique Laurent...; Heiner C. Bucher; Alexandra Calmy; Matthias Cavassini; Angela Ciuffi; Günter Dollenmaier; Mattias Egger; Luisa Elzi; Jan Fehr; Jacques Fellay; Hansjakob Furrer; Christoph A. Fux; Huldrych Fritz Gü...; Anna Hachfeld; David Haerry; Barbara Hasse; Hans H. Hirsch; Matthias Hoffmann; Irene Hösli; Michael Huber; David Jackson-Perry; Christian R. Kahlert; Laurent Kaiser; Olivia Keiser; Thomas Klimkait; Roger Dimitri Kouyos; Helen Kovari; Katharina Kusejko; Niklaus Labhardt; Karoline Leuzinger; Begogna Martinez ...; Catja Marzolini; Karin Jutta Metzner; Nicolas Müller; Johannes Nemeth; Dunja Nicca; Julia Notter; Paolo Paioni; Giuseppe Pantaleo; Matthieu Perreau; Andri Rauch; Luisa Salazar-Viz...; Patrick Schmid; Roberto Speck; Marcel Stöckle; Philip Tarr; Alexandra Trkola; Gilles Wandeler; Maja Weisser; Sabine Yerly; Alexandra Trkola; Huldrych F. Günthard; Roger D. Kouyos; Silvio D. Brugger; Benjamin G. Hale
• Keywords: Decoy

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 autoantibody–containing plasmas from aged individuals with HIV-1 and COVID-19. These overlap regions independently essential for engaging the IFNAR1/IFNAR2 heterodimer, efficiently block interaction of both receptor subunits in vitro. In contrast, non-neutralizing limit only one subunit display relatively low IFN-I–binding avidities, thus likely hindering function. Iterative engineering signaling-inert mutant IFN-Is (simIFN-Is) retaining autoantibody targets created potent decoys that prevent neutralization autoantibody-containing restore IFN-I–mediated antiviral activity. Additionally, microparticle-coupled simIFN-Is were effective at depleting autoantibodies plasmas, leaving antibodies unaffected. Our study reveals mechanisms action demonstrates a proof-of-concept strategy to alleviate pathogenic effects.