Year: 2026
Type: article
Study design: Observational Study
Abstract: Enteroviruses (EVs) have long been implicated in the development of islet autoimmunity (IA) and type 1 diabetes. However, given the ubiquity of EV infections in children, disease susceptibility is likely driven by host-specific immune responses rather than viral exposure alone. To investigate the host antibody response to EVs, we used virome-wide serological profiling (VirScan) to compare the EV antigen landscapes in IA-positive case children versus IA-negative control children across two independent pediatric cohorts separated by 12 years, using samples collected at the time point of seroconversion. We identified a reproducible and distinct EV-specific antibody signature in IA-positive case samples, with an enriched immunogenic hotspot localized within a highly conserved region in the 3D RNA-dependent RNA polymerase. Additionally, IA-positive male children exhibited significantly heightened antibody responses against a motif in the VP1 capsid protein compared with IA-negative male children (risk ratio 1.24; 95% CI 1.02, 1.52; P = 0.03). Our findings provide paradigm-shifting evidence that differential antiviral humoral responses, rather than the specific types of EV infection, play a central role in IA development, highlighting the need for an updated framework to study host-virus interactions in autoimmune pathogenesis. ARTICLE HIGHLIGHTS: Children positive for islet autoimmunity (IA) in two different Australian cohorts showed a distinct enterovirus (EV) antibody signature against specific regions of the EV genome polyprotein. A specific motif in the 3D region of the EV polyprotein was consistently enriched across cohorts and sexes, making it a potential marker for IA onset. Anti-VP1 motif antibody levels varied by sex, with significantly elevated levels in male children linked to early IA onset, highlighting possible sex-specific antiviral immunity. Findings support that host immune responses against EVs drive IA development, calling for a new framework to study host-virus interactions in IA.
Source: Diabetes
DOI: 10.2337/db25-0805
Authors: Beatriz Delgado-Corrales, Legana Fingerhut, Preston Leung, Cynthia S.A. Yau, Charles S.P. Foster, Emily J. Ward, Dylan B. Foskett, Aakash Annadurai, Simon C. Barry, Peter G. Colman, Jennifer J. Couper, Elizabeth A. Davis, Emma E. Hamilton-Williams, Leonard C. Harrison, Aveni Haynes, Tony Huynh, Kelly J. McGorm, Grant Morahan, Helena Oakey, Megan A.S. Penno, Georgia Soldatos, Rebecca L. Thomson, Jason A. Tye-Din, Peter J. Vuillermin, John M. Wentworth, Marc R. Wilkins, Jutta E. Laiho, Heikki Hyöty, William D. Rawlinson, Maria E. Craig, Ki Wook Kim, ENDIA Study Group
Institutions: UNSW Sydney, Prince of Wales Hospital, NSW Health Pathology, Women's and Children's Hospital, The University of Adelaide, The Royal Melbourne Hospital, The Kids Research Institute Australia, Princess Margaret Hospital for Children, Perth Children's Hospital, The University of Queensland, Walter and Eliza Hall Institute of Medical Research, The University of Western Australia, Children's Health Queensland Hospital and Health Service, Harry Perkins Institute of Medical Research, Monash Health, Monash University, Barwon Health, Deakin University, Tampere University, University of Tampere, Pirkanmaa Hospital District, Fimlab (Finland), Children's Hospital at Westmead
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
Funders: Leona M. and Harry B. Helmsley Charitable Trust, Juvenile Diabetes Research Foundation Australia, National Institutes of Health, University of California, San Francisco, Medical Research Council, National Health and Medical Research Council, National Institute of Allergy and Infectious Diseases
OpenAlex ID: W7128426118