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

• Applicant: Kathrin Maedler, Ph.D.
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 404665434

For many decades a link between viral infections, mainly by coxsackieviruses, and onset of type 1 diabetes (T1D) has been hypothesized, but how enteroviruses trigger β-cell destruction is poorly understood. Enteroviruses have been found in the pancreas –within and proximal to islets- from T1D patients and cause β-cell apoptosis and dysfunction. In this context, dendritic cells (DCs) are involved in the initiation of β-cell destruction in T1D by sensing exogenous stimuli, such as viruses or molecules like self nucleic acids. Our intriguing hypothesis is that islet-secreted miRNAs could act as modulators of inflammation in both innate and adaptive immune responses to environmental stress. MicroRNAs (miRNAs) are short nucleic acid molecules that reside within the cell, but also circulate through the body fluids.In our large miRNA array analysis in human pancreatic islets we have identified 3 miRNAs (mir-155, mir-146a, mir-146b), which are highly regulated in response to virus infection. The same miRNAs were also detected in a recent blood analysis from newly diagnosed patients with T1D, which provides the important link of enteroviruses- β-cell destruction- T1D. These miRNAs were proposed to act as immune-modulators through Toll like receptors (TLRs) in inflammatory diseases and to be transferred by exosomes for an immune-modulatory and metabolic cellular and organ-crosstalk. Such hypothesis will be proven in this project at the complex level of β-cell/ immune cell crosstalk.The aim of this project is to investigate the identified miRNAs in their role as modulators of the viral cycle in β-cells and activators of the host immune response through DCs. Thereby, we will investigate the β-cell inflammatory response and gene regulation as well as cell cycle and apoptotic cell death.This project will lead to the identification of so far unexplored miRNA-mediated effects on the immune attack towards β-cells and their subsequent destruction. Our pathways can ultimately be used for novel therapies of auto-immune disease, specifically for T1D.The strengths of this project are the already established cultures of diabetogenic viruses with human pancreatic islets, the identification of the mechanisms of virus specific β-cell infection and destruction as well as solid preliminary data from a miRNA screen of infected human islets.

• DFG Programme: Research Grants