Viral pathogenesis of type 1 diabetes - novel mechanisms and biomarker discovery

The mechanisms behind viral pathogenesis in type 1 diabetes (T1D) remain unclear. This project seeks to identify novel mechanisms and biomarkers related to β-cell infection. We investigate how enterovirus infection affects β-cell autophagy and extracellular vesicle (EV) secretion, and how viral dysregulation of these processes contributes to β-cell decay. Specifically, we examine changes in the autophagic transcriptome, β-cell function, and the EV proteome and miRNAome. We also explore the role of autophagy-driven EVs in viral spread and β-cell infection and their potential to activate dendritic cells and trigger β-cell autoimmunity. Additionally, we assess if circulating EVs could serve as biomarkers for viral infection in β-cells. Using cutting-edge technologies, state-of-the-art methods, and an integrative multi-omics systems biology approach, we aim to uncover key mechanisms linking viral infections to T1D. If viral dysregulation of the EV-autophagy network is confirmed as a key driver, targeting these pathways could offer new strategies to prevent or slow T1D progression.

Type 1 diabetes (T1D) is an autoimmune disease where the immune system mistakenly attacks and destroys insulin-producing β-cells in the pancreas. While genetics play a role, viral infections are suspected to trigger the disease, though the exact mechanism remains unclear.
Our research focuses on enteroviruses, a group of common viruses, and how they might disrupt key processes in β-cells, leading to their destruction. Cells have built-in systems to recycle damaged parts (called autophagy) and remove waste using tiny particles called extracellular vesicles (EVs). We’ve discovered that enteroviruses interfere with these systems, which may accelerate β-cell loss:
• Blocking autophagy: Enterovirus infection prevents β-cells from recycling damaged parts, leading to a buildup of cellular debris, increased virus production, and reduced insulin secretion, all of which contribute to β-cell destruction.
• Spreading infection: Disrupted autophagy causes infected β-cells to release more EVs containing virus particles, allowing the virus to spread to neighboring cells.
These findings suggest enteroviruses may play a larger role in T1D than previously thought. Our research is exploring several key questions:
• How does enterovirus infection affect β-cell recycling processes?
• Does infection alter the contents of EVs released by β-cells?
• Can EVs help spread the virus to other β-cells?
• Do infected β-cells signal the immune system, potentially triggering autoimmunity?
• Can EVs in the bloodstream serve as early markers of viral infection in β-cells?
By answering these questions, we aim to uncover how viruses contribute to T1D and identify potential early warning signs. If viral interference with these processes is key to β-cell destruction, it could lead to new treatments to prevent or slow T1D progression.