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, p<10-16) for auto-Abs neutralizing only 100 pg/mL IFN-alpha2 and/or IFN-omega to >2000 (OR=2218.4; 95% CI: 125.1-39337.7, p<10-16) for auto-Abs neutralizing high concentrations of IFN-alpha2 and high or low concentrations of IFN-omega. Pre-existing autoantibodies neutralizing type I IFNs are therefore causal for WNV encephalitis in about 40% of patients.

J.L.-C. is an inventor on patent application PCT/US2021/042741, filed July 22, 2021, submitted by The Rockefeller University and covering the diagnosis of susceptibility to, and the treatment of, viral disease, and viral vaccines, including COVID-19 and vaccine-associated diseases.

The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, The Rockefeller University, the St. Giles Foundation, the Stavros Niarchos Foundation (SNF) as part of its grant to the SNF Institute for Global Infectious Disease Research at The Rockefeller University, the National Institutes of Health (NIH) (R01AI163029), the National Center for Advancing Translational Sciences (NCATS), the NIH Clinical and Translational Science Award (CTSA) program (UL1TR001866), the French Agence Nationale de la Recherche (ANR) under the France 2030 program (ANR-10-IAHU-01), the HORIZON-HLTH-2024-DISEASE-08-20 program under GA 101191725 (InFlaMe), the ANRS projects DemeleJEV (ANRS0629) and LSDengue (ANRS-23-PEPR-MIE-0007), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU202503020018), ANR GENVIR (ANR-20-CE93-003), and ANR AI2D (ANR-22-CE15-0046) projects, the HORIZON-HLTH-2021-DISEASE-04 program under grant agreement 101057100 (UNDINE), the ANR-RHU COVIFERON Program (ANR-21-RHUS-0008), the Square Foundation, Grandir - Fonds de solidarite pour l'enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, the Battersea & Bowery Advisory Group, William E. Ford, General Atlantic's Chairman and Chief Executive Officer, Gabriel Caillaux, General Atlantic's Co-President, Managing Director and Head of Business in EMEA, and the General Atlantic Foundation, the French Ministry of Higher Education, Research, and Innovation (MESRI-COVID-19), Institut National de la Sante et de la Recherche Medicale (INSERM), REACTing-INSERM, Paris Cite University, and the Imagine Institute. P.B. was supported by a 'Poste CCA-INSERM-Bettencourt' (with support from the Bettencourt-Schueller Foundation), and the FRM (EA20170638020). A.G. was supported by a French National Agency for Research grant as part of the 'Investissement d'Avenir' program (ANR-10-LABX-62-01). The Host-pathogen group (A. Borghesi), Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, is supported by grants from the Italian Ministry of Health, RC08061819 and RC08061822, and by 5X1000 grant 08061821from the San Matteo Hospital. The Microbiology and Virology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, is supported by grants from the Ministry of Health, RC80206, and by the European Union under grant agreement 101191725 (InFlaMe project, HORIZON-HLTH-2024-DISEASE-08-20 program). A. Ferrari, at the Microbiology and Virology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, is affiliated to, and supported by, the National PhD Programme in One Health, Approaches to Infectious Diseases and Life Science Research, at the Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia, Italy, and by grant from the Italian Ministry of Health RC8048424. The Cell Factory (P. Comoli, M.A. Avanzini and S. Croce), at Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, is supported by grant from the Italian Ministry of Health RC8053724. The Department of Molecular Medicine, University of Padua, Italy, is supported by the European Union's Horizon 2020 research and innovation program (VEO, grant agreement 874735) and the EU4Health program (DURABLE, grant agreement101102733). The Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Italy, and the Department of Molecular Medicine, University of Padua, Italy, are supported by EU funding within the Next-Generation EU-MUR PNRR Extended Partnership initiative on Emerging Infectious Diseases (project no. PE00000007, INF-ACT). The Laboratory of Virology and Infectious Disease (M.R. MacDonald and C.M. Rice) is supported by NIH grants R01AI124690 and R01AI091707. The Murray laboratory is supported by NIH grants R01AI091816, U19AI089992.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics Committee of San Matteo Research Hospital in Pavia, Italy, EU (Comitato Etico Territoriale Lombardia 6 - Policlinico San Matteo) Ethics Committee of The University Hospital of Padua, Italy, EU Ethics Committee of The University Hospital of Bologna, Italy, EU Ethics Committee of Amedeo di Savoia Hospital-ASL Citta di Torino in Turin, Italy, EU Ethics Committee of the Tel-Aviv Sourasky Medical Center in Israel Ethics Committee of the National Public Health Center in Budapest Ethics Committee of the Rockefeller University in New York, USA The Center for Virology at the Medical University of Vienna, Austria, serves as the national reference center for arboviruses, and has the legal permission to process anonymized patient information on notifiable viral diseases

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Yes

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All data produced in the present study are available upon reasonable request to the authors