Autoantibodies neutralizing type I IFNs in 40% of patients with WNV encephalitis in seven new cohorts.

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Mosquito-borne West Nile virus (WNV) infection is a growing global health problem. About 0.5% of infected individuals develop encephalitis. We previously showed that 40% of patients in six cohorts had WNV encephalitis because of circulating auto-antibodies (auto-Abs) neutralizing type I IFNs. In seven new cohorts, we found that the prevalence of auto-Abs was highest (40% [17-44%]) in patients with encephalitis, and very low in a small sample of individuals with asymptomatic or mild infection. In the 13 European, Middle-Eastern and American cohorts available, odds ratios for WNV encephalitis in individuals with these auto-Abs relative to those without them in a large sample of the general population untested for WNV infection range from ~20 (OR=17.7; 95% CI: 13.8-22.8, <10) for auto-Abs neutralizing only 100 pg/mL IFN-α2 and/or IFN-ω to >2000 (OR=2218.4; 95% CI: 125.1-39337.7, <10) for auto-Abs neutralizing high concentrations of IFN-α2 and high or low concentrations of IFN-ω. Pre-existing autoantibodies neutralizing type I IFNs are therefore causal for WNV encephalitis in about 40% of patients. DOI: 10.1101/2025.08.31.25334556, PMID: 40950468
Authors: Adrian Gervais, Francesca Trespidi, Alessandro Ferrari, Francesca Rovida, Astrid Marchal, Stefania Croce, Irene Cassaniti, Mattia Moratti, Jennifer L Uhrlaub, David M Florian, Karin Stiasny, Elisa Burdino, Micol Angelini, Lucy Bizien, Daniele Lilleri, Veronica Codullo, Tal Freund, Yael Paran, Avi Gadoth, Roni Biran, Alessandro Mancon, Camilla Lucca, Stefania Vogiatzis, Monia Pacenti, Mélodie Aubart, Marco Zecca, Patrizia Comoli, Maria Antonietta Avanzini, Jacques Fellay, Antonio Piralla, Francesca Conti, Alberto Dolci, Luisa Barzon, Valeria Ghisetti, Tiziana Lazzarotto, Danilo Cereda, Alessandro Aiuti, Emmanuelle Jouanguy, Paul Bastard, Margaret R MacDonald, Charles M Rice, Anne Puel, Laurent Abel, Giada Rossini, Davide Mileto, Yannick Simonin, Anna Nagy, David Hagin, Kristy O Murray, Fausto Baldanti, Judith H Aberle, Aurélie Cobat, Shen-Ying Zhang, Jean-Laurent Casanova, Alessandro Borghesi