Servicenavigation

Project Details

Back

Projekt Print View

Tuning the inner-islet-immune cellular crosstalk in Type 1 Diabetes by enterovirus triggered miRNAs transferred in exosomes (Virus-Ex-beta)

Subject Area Endocrinology, Diabetology, Metabolism
Term from 2018 to 2023
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 404665434
 
Final Report Year 2023

Final Report Abstract

For more than a century, enteroviral infections have been associated with autoimmunity and Type 1 Diabetes (T1D) but this pathological link has been under debate since then. Only this year, in 2023, a large meta-analyses has just clarified that enteroviruses are clearly associated with autoimmunity and T1D, and anti-viral therapies in clinical trials against T1D have shown first promising results. This project has largely contributed to this confirmation. Within the virus group in the network for Pancreatic Organ Donors with diabetes (nPOD) we have obtained high quality pancreatic autopsies from well-characterized organ donors. By establishing and refining a single moleculebased fluorescent in situ hybridization (smFISH) method we detected increased viral RNA in pancreases from organ donors with T1D. Importantly, viral RNA is increased in pancreases from donors with disease associated autoantibodies (AAb+), suggesting viruses as early trigger for T1D disease onset and progression. Virus responses evoke chemokines and cytokines, the “cytokine storm” circulating through the body and attack cells especially vulnerable to inflammatory destruction. Intra-islet inflammation is a major trigger of beta-cell failure in both T1D and T2D. Therefore, we also analysed viral RNA in the pancreas of donors with T2D. In contrast to T1D, there was no difference in the presence or localization of enteroviral RNA in control nondiabetic and T2D pancreases; viral infiltration showed large heterogeneity in both groups scattered throughout the pancreas, again, most of them in the exocrine pancreas. Very rarely, a single virus+ cell was found within islets or co-stained with CD45+ immune cells. Despite great similarities in inflammatory markers in islets in T1D and T2D, long-term enteroviral infiltration is a distinct pathological feature of T1D-associated autoimmunity and in T1D pancreases. How enteroviruses trigger β-cell destruction is still poorly understood. Stemming from our initial miRNA screen we found three miRNAs (miR155, miR146a, miR146b) highly upregulated in human islets in response to virus infection. We hypothesized that islet-secreted miRNAs could act as modulators of inflammation in both innate and adaptive immune responses to environmental stress. We found that these miRNAs were indeed upregulated in exosomes from enterovirus-infected islets. Transfer of vesicles from infected islets to islets or to monocytes modulated enterovirus-induced inflammation and beta-cell death. The overall increased proportion of virus-positive cells in the pancreas of AAb+ and T1D organ donors suggest that enteroviruses are indeed associated with immune cell infiltration, autoimmunity and b-cell destruction in both preclinical and diagnosed T1D and not only the virus itself but also circulating miRNAs after infection may induce the progression of T1D.

Publications

 
 

Additional Information

© 2025 DFG Disclaimer / Copyright / Privacy Policy

Textvergrößerung und Kontrastanpassung