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Richardson, S.J.* ; Rodriguez-Calvo, T. ; Laiho, J.E.* ; Kaddis, J.S.* ; Nyalwidhe, J.O.* ; Kusmartseva, I.* ; Morfopoulou, S.* ; Petrosino, J.F.* ; Plagnol, V.* ; Maedler, K.* ; Morris, M.A.* ; Nadler, J.L.* ; Atkinson, M.A.* ; von Herrath, M.* ; Lloyd, R.E.* ; Hyöty, H.* ; Morgan, N.G.* ; Pugliese, A.*

Joint analysis of the nPOD-Virus Group data: The association of enterovirus with type 1 diabetes is supported by multiple markers of infection in pancreas tissue.

Diabetologia 68, 1226-1241 (2025)

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AIMS/HYPOTHESIS: Previous pathology studies have associated enterovirus infections with type 1 diabetes by examining the enterovirus capsid protein 1 (VP1) in autopsy pancreases obtained near diabetes diagnosis. The Network for Pancreatic Organ Donors with Diabetes (nPOD) has since obtained pancreases from organ donors with type 1 diabetes (with broad age and disease duration) and donors with disease-associated autoantibodies (AAbs), the latter representing preclinical disease. Two accompanying manuscripts from the nPOD-Virus Group report primary data from a coordinated analysis of multiple enterovirus indices. We aimed to comprehensively assess the association of multiple enterovirus markers with type 1 diabetes. METHODS: The nPOD-Virus Group examined pancreases from 197 donors, recovered between 2007 and 2019, classified into five groups: donors with type 1 diabetes, with residual insulin-containing islets (T1D-ICI group, n=41) or with only insulin-deficient islets (T1D-IDI, n=42); donors without diabetes who are AAb-negative (ND, n=83); and rare donors without diabetes expressing a single AAb (AAb⁺, n=22) or multiple AAbs (AAb⁺⁺, n=9). We assessed the overall association of multiple indicators of enterovirus infection, case-by-case and between donor groups, as well as assay agreement and reproducibility, using various statistical methods. We examined data from 645 assays performed across 197 nPOD donors. RESULTS: Detection of enterovirus indices by independent laboratories had high reproducibility, using both enterovirus-targeted and unbiased methods. T1D-ICI donors had significantly higher (p<0.001) proportions of positive assay outcomes (58.4%) vs T1D-IDI (10.3%), ND (17.8%) and AAb-positive donors (AAb⁺ 24.6%; AAb⁺⁺ 35.0%). Head-to-head comparisons revealed increased proportions of donors positive in two independent assays among T1D-ICI vs ND donors (VP1/HLA class I [HLA-I], p<0.0001; VP1/enterovirus-specific RT-PCR (EV-PCR), p=0.076; EV-PCR/HLA-I, p=0.016; proteomics/HLA-I, p<0.0001; VP1/proteomics, p=0.06). Among 110 donors examined for three markers (VP1, EV-PCR and HLA-I), 83.3% of T1D-ICI donors were positive in two or more assays vs 0% of ND (p<0.001), 26.7% of AAb⁺ (p=0.006), 28.6% of AAb⁺⁺ (p=0.023) and 0% of T1D-IDI (p<0.001) donors. CONCLUSIONS/INTERPRETATION: The nPOD-Virus Group conducted, to date, the largest and most comprehensive analysis of multiple indices of pancreatic enterovirus infections in type 1 diabetes; these were more prevalent in T1D-ICI and AAb⁺⁺ donors than in other groups. Their preferential detection of these indices in donors with residual beta cells and autoimmunity implicates enterovirus infections across disease progression stages and supports a contribution to beta cell loss, directly or indirectly, even after diagnosis. The relatively small number of infected cells and the low amount of viral RNA support the existence of non-acute, low level, possibly persistent enterovirus infections in the pancreas.

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