Distinct Enterovirus Antigen Landscape in Children With Islet Autoimmunity

Delgado-Corrales, B; LEUNG, P; Fingerhut, L; Hyoty, H; ENDIA Study Group; Yau, CSA; Foster, CSP; Ward, EJ; Foskett, DB; Annadurai, A; Barry, SC; Colman, PG; Couper, JJ; Davis, EA; Hamilton-Williams, EE; Harrison, LC; Haynes, A; Huynh, T; McGorm, KJ; Morahan, G; Oakey, H; Penno, MAS; Soldatos, G; Thomson, RL; Tye-Din, JA; Vuillermin, PJ; Wentworth, JM; Wilkins, MR; Laiho, JE; Rawlinson, WD; Craig, ME; Kim, KW

Author(s): Delgado-Corrales, B; LEUNG, P; Fingerhut, L; Hyoty, H; ENDIA Study Group; Yau, CSA; Foster, CSP; Ward, EJ; Foskett, DB; Annadurai, A; Barry, SC; Colman, PG; Couper, JJ; Davis, EA; Hamilton-Williams, EE; Harrison, LC; Haynes, A; Huynh, T; McGorm, KJ; Morahan, G; Oakey, H; Penno, MAS; Soldatos, G; Thomson, RL; Tye-Din, JA; Vuillermin, PJ; Wentworth, JM; Wilkins, MR; Laiho, JE; Rawlinson, WD; Craig, ME; Kim, KW;
Details: Publication Year 2026-04-01,Volume 75,Issue #4,Page 738-747
Journal Title: Diabetes
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.
Publisher: ADA
Keywords: Humans; Child; Male; *Autoimmunity/immunology; *Enterovirus/immunology; Female; *Enterovirus Infections/immunology; *Diabetes Mellitus, Type 1/immunology/virology; *Islets of Langerhans/immunology; Child, Preschool; *Antigens, Viral/immunology; Adolescent; Antibodies, Viral/immunology/blood
Research Division(s): Immunology
PubMed ID: 41662565
Publisher's Version: https://doi.org/10.2337/db25-0805
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-03-16 01:38:24

Last Modified: 2026-03-24 02:18:09