Enterovirus-linked Type 1 Diabetes exposed - mechanisms and prevention (ENT1DEP)

ENT1DEP aims to define causal links between infections and noncommunicable diseases (NCDs) by focusing on enterovirus (EV) infections and type 1 diabetes (T1D), a robust association without proof of causality. Causality is addressed by a multidisciplinary, multi-layer approach, using in-vitro and in-vivo models, unique human samples, and artificial intelligence to identify mechanisms and related biomarkers, asking 3 key questions:

1. Why are only insulin-producing β-cells destroyed by EVs? Weak β-cell antiviral responses and high expression of EV entry receptors may favour EV persistence. This hypothesis is addressed using human cell models (stem-cell-derived β/α-cells, organoids, their genetic modifications, anti-EV T-cells) and pancreas tissues from T1D patients.
2. Why do only some individuals develop T1D after EV infection? Weak EV immunity may predispose to virus spreading to pancreas, persistence and local inflammation, triggering autoimmunity. This hypothesis is addressed by analysing adaptive and innate immune responses to EVs, correlating these with gene polymorphisms and EV persistence in children followed from birth and who developed T1D.
3. How can EV associated T1D risk be attenuated? By using vaccines inducing protective immunity and antiviral drugs eradicating persistent infection. This hypothesis is addressed by examining samples from pioneering EV vaccine and T1D antiviral trials to develop biomarkers of vaccine- vs infection-induced immunity as surrogates of vaccine efficacy; by studying whether vaccine-induced antibodies prevent EV-induced diabetes in mice; by correlating antiviral treatment with EV clearance and immunity to identify biomarkers for EV eradication and patient selection.

The final goal is to identify individuals at risk for EV-induced T1D as targets for early interventions. These outcomes may also facilitate progress in other NCDs extending impact. This new knowledge is disseminated among stakeholders to facilitate optimal NCD prevention and treatment.