Beatriz Delgado-Corrales, Legana C H W Fingerhut, Leung Preston, 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, L. 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 Wilkins, Jutta E. Laiho, Heikki Hyöty, William D. Rawlinson, Maria E. Craig, Ki Wook Kim, ENDIA Study Group*
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.