New study links persistent enterovirus infection to onset and progression of type 1 diabetes

May 28, 2025 — 08:00 🕑 6 minutes

New study links persistent enterovirus infection to onset and progression of type 1 diabetes

Viruses are increasingly being explored as contributors to chronic diseases, including in diabetes research.

This has been supported by birth cohort studies of individuals with a genetic risk of type 1 diabetes (T1D), as well as by pancreas autopsies of organs collected at the time of diagnosis.

Among potential viral candidates, enteroviruses have emerged as a promising area of research. A recent study published in Diabetologia now presents a comprehensive assessment of enterovirus-related markers in donor organs at different stages of T1D. By combining multiple viral indicators, the international team found evidence to support the hypothesis that chronic or recurrent enteroviral infections may contribute to the pathophysiology of T1D.

Persistent, low-level infection suspected

“We have confirmed the presence of enteroviral proteins, using both targeted and unbiased approaches, and importantly also provided evidence of enteroviral genomic material in different assays. This supports the hypothesis of a persistent, low-level productive infection,” says co-author Teresa Rodriguez‑Calvo, group leader at the Type 1 Diabetes Pathology Research Unit at Helmholtz Diabetes Center Munich and EASD Member.

Rather than any single enterovirus marker, “it is the combination of viral markers that provide the strongest support for an association with T1D,” adds first author Sarah J. Richardson, Professor of Cellular Biomedicine at the University of Exeter Medical School and also EASD member.

The results show a significantly higher frequency of enterovirus marker detection in two donor groups: (1) individuals with T1D who still had residual insulin-producing islets, and (2) donors in the preclinical stage who expressed diabetes-associated autoantibodies (AAbs). These findings suggest a T1D-enterovirus association irrespective of disease duration and support further research on preventive and therapeutic strategies.

Nearly 200 donor organs examined

The study analysed assays by the international Network for Pancreatic Organ Donors with Diabetes (nPOD). A total of 197 donor organs, recovered between 2007 and 2019, were analysed across multiple laboratories, yielding 645 assay results. Donors were categorised into five groups:

T1D-ICI: donors with type 1 diabetes and residual insulin-containing islets
T1D-IDI: donors with type 1 diabetes with only insulin-deficient islets
ND: donors without diabetes who are AAb-negative
AAb+: rare donors without diabetes expressing a single AAb
AAb++: rare donors without diabetes expressing multiple AAbs

Comprehensive assessment of enterovirus markers

To detect enterovirus infection, the study used a combination of assays for viral proteins (e.g. the capsid protein VP1), viral RNA, and hyperexpression of HLA class I as an indicator of interferon-α signalling triggered by infection.

Of all donor groups, T1D-ICI showed the highest proportion of positive outcomes (60 % vs. 10–38 % in the other groups; p < 0.05–0.001). Among the 110 donors tested with the three most informative assays (VP1, enterovirus-specific RT-PCR, and HLA-I), 83.3 % of T1D-ICI donors were positive in at least two assays – compared to none in the ND and T1D-IDI groups, 26.7 % in the AAb+ group and 28.6 % in the AAb++ group (Figure 1). Another analysis confirmed that donors with islet autoimmunity (defined by circulating AAbs and/or insulitis) and residual beta cells had significantly higher rates of multiple positive enterovirus markers (Figure 1).

Figure 1: Proportions of donors positive in at least two independent assays compared by donor classification and presence of autoimmunity (AI, defined by circulating autoantibodies and/or insulitis) or residual beta cells.

Infection as a driver of autoimmunity

“Enteroviral infections are very common in child- and adulthood. We hypothesise that the virus is able to infect pancreatic beta cells and cause cell death,” says Rodriguez‑Calvo. “Dead cells would release beta cell antigens and trigger antigen-presentation within the islets and the draining pancreatic lymph nodes, resulting in the recruitment of immune cells to the pancreas.”

Richardson adds: “In individuals at risk of developing type 1 diabetes, recruitment of self-reactive, beta-cell-targeted immune cells could be sufficient to initiate autoimmunity. Our findings support a persistent, low-level enteroviral infection, which could contribute to a proinflammatory environment within affected islets where cytokines like interferons are secreted. This could support a continued and progressive autoimmunity and targeted beta cell destruction throughout disease stages 1 to 4.”

Why focus on enterovirus?

The authors summarise a range of previous findings that support an association between enterovirus and T1D, including the association of maternal enterovirus infection during pregnancy with T1D in offspring and the finding that, in genetically at-risk children, enterovirus RNA and neutralising antibodies appear before islet autoantibodies.

“Enteroviruses were a focus of the targeted strategies of our study based on evidence from extensive epidemiological studies that have associated enteroviral infections with type 1 diabetes related autoimmunity and progression to clinical onset,” says Rodriguez‑Calvo. „Furthermore, and crucially, certain enteroviral serotypes – particularly Coxsackie B family members – have a propensity to readily and selectively infect human pancreatic beta cells.”

Clinical implications: screening, prevention, treatment

While the detection of viral markers in pancreatic tissue provides valuable insights, it poses challenges for use in routine prognostic screening. However, the authors suggest that markers of antiviral immune responses in blood may offer alternatives. They point to examples like the AVAnT1A clinical trial (Hummel et al., 2025), which screens blood for more than 20 viruses to explore T1D prevention via vaccination in children.

“In the field of prevention, it will be important to trial enterovirus vaccination approaches – for example the multi-valent coxsackie B virus vaccine recently reported in phase I safety trials – to determine if this could prevent diabetes-related autoimmunity and clinical onset in genetically at-risk individuals,” says Rodriguez‑Calvo.

Additionally, therapeutic strategies are needed. A phase II clinical trial reported that early antiviral treatment may help preserve insulin production when administered close to the time of T1D diagnosis (Krogvold et al., 2023). However, Richardson points out that there are practical factors to be considered: “Although there are agents that are effective against acute, lytic enteroviral infections, we will need to identify agents that are effective against a persistent enterovirus infection. This will require the development of appropriate cellular models in which to test them.”

While the study results offer valuable insights, the question of whether enteroviruses infect the pancreas as a whole or specifically target beta cells remains unanswered. What is certain is that viruses will continue to be a compelling focus of future research into the origins, prevention and treatment of type 1 diabetes.

Key Points:
In this study, enterovirus markers were significantly increased in organ donors with type 1 diabetes or diabetes-associated antibodies, supporting a potential role in disease pathogenesis.
Persistent, low-level enteroviral infection may create a proinflammatory environment and trigger beta cell-targeted autoimmunity.
Multiple viral indicators combined (VP1, viral RNA, HLA-I) provided the strongest link between enterovirus and T1D across donor groups.
Future prevention and treatment strategies may include targeted vaccines or antivirals, but challenges remain in treating persistent infections and translating findings into screening tools.

To read this paper visit: Richardson, S.J., Rodriguez-Calvo, T., Laiho, J.E. et al. 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 (2025).

Author: Hanna Gabriel, BA MSc. Any opinions expressed in this article are the responsibility of EASD e-Learning.