Edited by Peter M. Palese, Icahn School of Medicine at Mount Sinai, New York, NY; received May 12, 2026; accepted July 18, 2026
Significance
Chikungunya virus (CHIKV) infection results in life-threatening central nervous system (CNS) complications in rare cases. We found that autoantibodies neutralizing type I interferons underlie severe CNS CHIKV infection in 35% of the patients tested. These autoantibodies have previously been shown to underlie encephalitis following live-attenuated CHIKV vaccination and an increasing number of other severe arboviral infections. Screening for such autoantibodies is essential for individuals living in regions endemic for CHIKV and other arboviruses and for devising effective therapeutic strategies for affected patients.
Abstract
Chikungunya virus (CHIKV) infection is typically not life threatening but may, in rare cases, affect the central nervous system (CNS). In three cohorts of confirmed CHIKV cases from Martinique (French overseas territory) and Brazil (patients aged 0 to 89 y, n = 245), 20 patients had CNS infection (aged 17 to 87 y). Autoantibodies neutralizing type I interferons (AAN-I-IFN) were found in 35% of patients (4 male and 3 female, aged 17 to 87 y) with encephalitis (4/15), encephalomyelitis (1/2), or myelitis (2/3), but were absent in 225 patients without CNS infection. They neutralized high concentrations (10 to 1,000 ng/mL) of IFN-α2, IFN-α8, and IFN-ω, and the antibodies of one patient also neutralized IFN-β. All samples also neutralized the other 10 IFN-α subtypes (at least 100 pg/mL). This combination of blood autoantibodies occurs in ~0.02% and 0.6% of healthy individuals under and over 70 y of age, respectively. The presence of AAN-I-IFN before CHIKV infection therefore increased the risk of CNS disease ~850-fold relative to the general population.
Data, Materials, and Software Availability
All study data are included in the main text.
Acknowledgments
We thank the patients and their families for participating in our research. We thank all members of both branches of the Laboratory of Human Genetics of Infectious Diseases for discussions and technical and administrative support. We thank Lazaro Lorenzo and Yelena Nemirovskaya for administrative assistance. 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 NIH (R01AI163029), the National Center for Advancing Translational Sciences, the NIH Clinical and Translational Science Award 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 DéméléJEV (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), ANR AI2D (ANR-22-CE15-0046), 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 solidarité 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), INSERM, REACTing-INSERM, Paris Cité 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). We thank the Centre de Ressources Biologiques de Martinique CHU Martinique, France, ID number BRIF BB-0033-00099, for managing patient samples. The CARBO cohort was supported by a grant from the Clinical Research Hospital Program from the French Ministry of Health (PHRC “2009”).
Author contributions
V.L.T., A.G., M.-M.C., A. Cobat, S.-Y.Z., and J.-L.C. designed research; V.L.T., A.G., M.-M.C., M.P.d.S.S., S.A., I.C., M.S.d.R., L.S., J.D.S., P.A.A., A.P., P.B., L.A., C.P., R.F.d.O.F., I.C.d.S., A. Cabié, A. Cobat, and S.-Y.Z. performed research; V.L.T., A.G., M.-M.C., A. Cobat, S.-Y.Z., and J.-L.C. analyzed data; and V.L.T., A.G., A. Cobat, S.-Y.Z., and J.-L.C. wrote the paper.
Competing interests
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 treatment of, viral disease, and viral vaccines, including COVID-19 and vaccine-associated diseases.
References
1
O. Schwartz, M. L. Albert, Biology and pathogenesis of chikungunya virus. Nat. Rev. Microbiol. 8, 491–500 (2010).
2
J. E. Staples, M. Fischer, Chikungunya virus in the Americas—What a vectorborne pathogen can do. N. Engl. J. Med. 371, 887–889 (2014).
3
H. Zeller, W. Van Bortel, B. Sudre, Chikungunya: Its history in Africa and Asia and its spread to new regions in 2013–2014. J. Infect. Dis. 214, S436–S440 (2016).
4
T.-Y. Wang, Y. Sun, Y.-D. Tang, Re-emergence of chikungunya virus in China by 2025: What we know and what to do? PLoS Pathog. 21, e1013556 (2025).
5
W. M. de Souza et al., Chikungunya: A decade of burden in the Americas. Lancet Reg. Health Am. 30, 100673 (2024).
6
J. E. Staples, R. F. Breiman, A. M. Powers, Chikungunya fever: An epidemiological review of a re-emerging infectious disease. Clin. Infect. Dis. 49, 942–948 (2009).
7
G. Ribeiro dos Santos et al., Global burden of chikungunya virus infections and the potential benefit of vaccination campaigns. Nat. Med. 31, 2342–2349 (2025).
8
K. Rama et al., Clinical outcomes of chikungunya: A systematic literature review and meta-analysis. PLoS Negl. Trop. Dis. 18, e0012254 (2024).
9
T. Das et al., Chikungunya fever: CNS infection and pathologies of a re-emerging arbovirus. Prog. Neurobiol. 91, 121–129 (2010).
10
M. Mendonça, A. Cabral, H. Lacerda, Factors associated with death from dengue and chikungunya virus infection during an epidemic period in Northeast Brazil: A retrospective cohort study. Rev. Soc. Bras. Med. Trop. 56, e0030 (2023).
11
P. Gerardin et al., Chikungunya virus-associated encephalitis: A cohort study on La Reunion Island, 2005–2009. Neurology 86, 94–102 (2016).
12
J. O. M. Bentvelzen et al., Clinical outcomes of chikungunya across age groups: A systematic review. PLoS Negl. Trop. Dis. 19, e0013580 (2025).
13
A. Gervais, A. Borghesi, J.-L. Casanova, S.-Y. Zhang, Auto-Abs against type I IFNs: Strong, common, and global determinants of severe arboviral diseases. J. Hum. Immun. 2, e20250090 (2025).
14
A. Gervais et al., Auto-Abs neutralizing type I IFNs in patients with severe Powassan, Usutu, or Ross River virus disease. J. Exp. Med. 221, e20240942 (2024).
15
A. Gervais et al., Autoantibodies neutralizing type I IFNs underlie severe tick-borne encephalitis in ~10% of patients. J. Exp. Med. 221, e20240637 (2024).
16
A. Gervais et al., Autoantibodies neutralizing type I IFNs underlie West Nile virus encephalitis in approximately 40% of patients. J. Exp. Med. 220, e20230661 (2023).
17
J. L. Casanova, Human immunity. J. Hum. Immun. 1, e20250001 (2025).
18
J. L. Casanova, Toward a monogenic architecture of human infections: From 1996 to 2026. J. Hum. Immun. 2, e20260027 (2026).
19
J. A. Jensen et al., Autoantibodies neutralizing type 1 interferons in two cohorts of people with HIV. J. Hum. Immun. 2, e20250179 (2026).
20
A. Gervais et al., Type I IFN autoantibodies underlie chikungunya live-attenuated vaccine encephalitis. Proc. Natl. Acad. Sci. U.S.A. 123, e2532212123 (2026).
21
M. L. Brito Ferreira et al., Neurological disease in adults with Zika and chikungunya virus infection in Northeast Brazil: A prospective observational study. Lancet Neurol. 19, 826–839 (2020).
22
M. S. D. Rosario et al., Predominance of arboviruses in acute encephalitis and Guillain-Barre syndrome: Findings from a prospective cohort in Northeast Brazil. Int. J. Infect. Dis. 168, 108664 (2026).
23
K. Groen et al., Highly-sensitive reporter cell line for detection of interferon types I-III and their neutralization by antibodies. Eur. J. Immunol. 54, 2451325 (2024).
24
M. Postal et al., Type I interferon in the pathogenesis of systemic lupus erythematosus. Curr. Opin. Immunol. 67, 87–94 (2020).
25
P. Bastard et al., Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths. Sci. Immunol. 6, eabl4340 (2021).
26
S. Eto et al., Neutralizing type I interferon autoantibodies in Japanese patients with severe COVID-19. J. Clin. Immunol. 42, 1360–1370 (2022).
27
S. Fernbach et al., Loss of tolerance precedes triggering and lifelong persistence of pathogenic type I interferon autoantibodies. J. Exp. Med. 221, e20240365 (2024).
28
G. Uze, G. Lutfalla, I. Gresser, Genetic transfer of a functional human interferon alpha receptor into mouse cells: Cloning and expression of its cDNA. Cell 60, 225–234 (1990).
29
D. Novick, B. Cohen, M. Rubinstein, The human interferon alpha/beta receptor: Characterization and molecular cloning. Cell 77, 391–400 (1994).
30
B. Cohen, D. Novick, S. Barak, M. Rubinstein, Ligand-induced association of the type I interferon receptor components. Mol. Cell. Biol. 15, 4208–4214 (1995).
31
G. Lutfalla et al., Mutant U5A cells are complemented by an interferon-alpha beta receptor subunit generated by alternative processing of a new member of a cytokine receptor gene cluster. EMBO J. 14, 5100–5108 (1995).
32
A. Gervais et al., Autoantibodies neutralizing type I IFNs in 40% of patients with WNV encephalitis in seven new cohorts. J. Hum. Immun. 2, e20250189 (2026).
33
K. Groen, B. G. Hale, Human autoantibodies against type I interferons in severe viral disease. Curr. Opin. Virol. 74, 101511 (2026).
34
M. Fournier et al., Affinity-matured B cell responses neutralizing type-I interferons underlie severe viral infections. Cell 189, 3236–3253.e23 (2026).
35
S. Gupta et al., Distinct functions of autoantibodies against interferon in systemic lupus erythematosus: A comprehensive analysis of anticytokine autoantibodies in common rheumatic diseases. Arthritis Rheumatol. 68, 1677–1687 (2016).
36
P. Bastard et al., Auto-antibodies to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine. J. Exp. Med. 218, e20202486 (2021).
37
J. J. Peng et al., Chimeric autoantibody receptor T cells clonally eliminate B cells producing autoantibodies against IFN-gamma. Sci. Immunol. 10, eadm8186 (2025).
38
K. Groen et al., Type I interferon autoantibody footprints reveal neutralizing mechanisms and allow inhibitory decoy design. J. Exp. Med. 222, e20242039 (2025).
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Copyright © 2026 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).
Data, Materials, and Software Availability
All study data are included in the main text.
Submission history
Received: May 12, 2026
Accepted: July 18, 2026
Published online: August 17, 2026
Published in issue: August 25, 2026
Keywords
Acknowledgments
We thank the patients and their families for participating in our research. We thank all members of both branches of the Laboratory of Human Genetics of Infectious Diseases for discussions and technical and administrative support. We thank Lazaro Lorenzo and Yelena Nemirovskaya for administrative assistance. 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 NIH (R01AI163029), the National Center for Advancing Translational Sciences, the NIH Clinical and Translational Science Award 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 DéméléJEV (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), ANR AI2D (ANR-22-CE15-0046), 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 solidarité 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), INSERM, REACTing-INSERM, Paris Cité 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). We thank the Centre de Ressources Biologiques de Martinique CHU Martinique, France, ID number BRIF BB-0033-00099, for managing patient samples. The CARBO cohort was supported by a grant from the Clinical Research Hospital Program from the French Ministry of Health (PHRC “2009”).
Author contributions
V.L.T., A.G., M.-M.C., A. Cobat, S.-Y.Z., and J.-L.C. designed research; V.L.T., A.G., M.-M.C., M.P.d.S.S., S.A., I.C., M.S.d.R., L.S., J.D.S., P.A.A., A.P., P.B., L.A., C.P., R.F.d.O.F., I.C.d.S., A. Cabié, A. Cobat, and S.-Y.Z. performed research; V.L.T., A.G., M.-M.C., A. Cobat, S.-Y.Z., and J.-L.C. analyzed data; and V.L.T., A.G., A. Cobat, S.-Y.Z., and J.-L.C. wrote the paper.
Competing interests
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 treatment of, viral disease, and viral vaccines, including COVID-19 and vaccine-associated diseases.
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This article is a PNAS Direct Submission.
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Autoantibodies neutralizing type I interferons underlie a third of cases of Chikungunya virus encephalitis or myelitis, Proc. Natl. Acad. Sci. U.S.A.
123 (34) e2616897123,
https://doi.org/10.1073/pnas.2616897123
(2026).
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References
References
1
O. Schwartz, M. L. Albert, Biology and pathogenesis of chikungunya virus. Nat. Rev. Microbiol. 8, 491–500 (2010).
2
J. E. Staples, M. Fischer, Chikungunya virus in the Americas—What a vectorborne pathogen can do. N. Engl. J. Med. 371, 887–889 (2014).
3
H. Zeller, W. Van Bortel, B. Sudre, Chikungunya: Its history in Africa and Asia and its spread to new regions in 2013–2014. J. Infect. Dis. 214, S436–S440 (2016).
4
T.-Y. Wang, Y. Sun, Y.-D. Tang, Re-emergence of chikungunya virus in China by 2025: What we know and what to do? PLoS Pathog. 21, e1013556 (2025).
5
W. M. de Souza et al., Chikungunya: A decade of burden in the Americas. Lancet Reg. Health Am. 30, 100673 (2024).
6
J. E. Staples, R. F. Breiman, A. M. Powers, Chikungunya fever: An epidemiological review of a re-emerging infectious disease. Clin. Infect. Dis. 49, 942–948 (2009).
7
G. Ribeiro dos Santos et al., Global burden of chikungunya virus infections and the potential benefit of vaccination campaigns. Nat. Med. 31, 2342–2349 (2025).
8
K. Rama et al., Clinical outcomes of chikungunya: A systematic literature review and meta-analysis. PLoS Negl. Trop. Dis. 18, e0012254 (2024).
9
T. Das et al., Chikungunya fever: CNS infection and pathologies of a re-emerging arbovirus. Prog. Neurobiol. 91, 121–129 (2010).
10
M. Mendonça, A. Cabral, H. Lacerda, Factors associated with death from dengue and chikungunya virus infection during an epidemic period in Northeast Brazil: A retrospective cohort study. Rev. Soc. Bras. Med. Trop. 56, e0030 (2023).
11
P. Gerardin et al., Chikungunya virus-associated encephalitis: A cohort study on La Reunion Island, 2005–2009. Neurology 86, 94–102 (2016).
12
J. O. M. Bentvelzen et al., Clinical outcomes of chikungunya across age groups: A systematic review. PLoS Negl. Trop. Dis. 19, e0013580 (2025).
13
A. Gervais, A. Borghesi, J.-L. Casanova, S.-Y. Zhang, Auto-Abs against type I IFNs: Strong, common, and global determinants of severe arboviral diseases. J. Hum. Immun. 2, e20250090 (2025).
14
A. Gervais et al., Auto-Abs neutralizing type I IFNs in patients with severe Powassan, Usutu, or Ross River virus disease. J. Exp. Med. 221, e20240942 (2024).
15
A. Gervais et al., Autoantibodies neutralizing type I IFNs underlie severe tick-borne encephalitis in ~10% of patients. J. Exp. Med. 221, e20240637 (2024).
16
A. Gervais et al., Autoantibodies neutralizing type I IFNs underlie West Nile virus encephalitis in approximately 40% of patients. J. Exp. Med. 220, e20230661 (2023).
17
J. L. Casanova, Human immunity. J. Hum. Immun. 1, e20250001 (2025).
18
J. L. Casanova, Toward a monogenic architecture of human infections: From 1996 to 2026. J. Hum. Immun. 2, e20260027 (2026).
19
J. A. Jensen et al., Autoantibodies neutralizing type 1 interferons in two cohorts of people with HIV. J. Hum. Immun. 2, e20250179 (2026).
20
A. Gervais et al., Type I IFN autoantibodies underlie chikungunya live-attenuated vaccine encephalitis. Proc. Natl. Acad. Sci. U.S.A. 123, e2532212123 (2026).
21
M. L. Brito Ferreira et al., Neurological disease in adults with Zika and chikungunya virus infection in Northeast Brazil: A prospective observational study. Lancet Neurol. 19, 826–839 (2020).
22
M. S. D. Rosario et al., Predominance of arboviruses in acute encephalitis and Guillain-Barre syndrome: Findings from a prospective cohort in Northeast Brazil. Int. J. Infect. Dis. 168, 108664 (2026).
23
K. Groen et al., Highly-sensitive reporter cell line for detection of interferon types I-III and their neutralization by antibodies. Eur. J. Immunol. 54, 2451325 (2024).
24
M. Postal et al., Type I interferon in the pathogenesis of systemic lupus erythematosus. Curr. Opin. Immunol. 67, 87–94 (2020).
25
P. Bastard et al., Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths. Sci. Immunol. 6, eabl4340 (2021).
26
S. Eto et al., Neutralizing type I interferon autoantibodies in Japanese patients with severe COVID-19. J. Clin. Immunol. 42, 1360–1370 (2022).
27
S. Fernbach et al., Loss of tolerance precedes triggering and lifelong persistence of pathogenic type I interferon autoantibodies. J. Exp. Med. 221, e20240365 (2024).
28
G. Uze, G. Lutfalla, I. Gresser, Genetic transfer of a functional human interferon alpha receptor into mouse cells: Cloning and expression of its cDNA. Cell 60, 225–234 (1990).
29
D. Novick, B. Cohen, M. Rubinstein, The human interferon alpha/beta receptor: Characterization and molecular cloning. Cell 77, 391–400 (1994).
30
B. Cohen, D. Novick, S. Barak, M. Rubinstein, Ligand-induced association of the type I interferon receptor components. Mol. Cell. Biol. 15, 4208–4214 (1995).
31
G. Lutfalla et al., Mutant U5A cells are complemented by an interferon-alpha beta receptor subunit generated by alternative processing of a new member of a cytokine receptor gene cluster. EMBO J. 14, 5100–5108 (1995).
32
A. Gervais et al., Autoantibodies neutralizing type I IFNs in 40% of patients with WNV encephalitis in seven new cohorts. J. Hum. Immun. 2, e20250189 (2026).
33
K. Groen, B. G. Hale, Human autoantibodies against type I interferons in severe viral disease. Curr. Opin. Virol. 74, 101511 (2026).
34
M. Fournier et al., Affinity-matured B cell responses neutralizing type-I interferons underlie severe viral infections. Cell 189, 3236–3253.e23 (2026).
35
S. Gupta et al., Distinct functions of autoantibodies against interferon in systemic lupus erythematosus: A comprehensive analysis of anticytokine autoantibodies in common rheumatic diseases. Arthritis Rheumatol. 68, 1677–1687 (2016).
36
P. Bastard et al., Auto-antibodies to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine. J. Exp. Med. 218, e20202486 (2021).
37
J. J. Peng et al., Chimeric autoantibody receptor T cells clonally eliminate B cells producing autoantibodies against IFN-gamma. Sci. Immunol. 10, eadm8186 (2025).
38
K. Groen et al., Type I interferon autoantibody footprints reveal neutralizing mechanisms and allow inhibitory decoy design. J. Exp. Med. 222, e20242039 (2025).