Abstract
Coxsackievirus B (CVB) is implicated as an environmental trigger for type 1 diabetes (T1D). While CVB impairs islet function and viability, its impact on individual primary human islet cell types remains unclear. Here, we use single-cell RNA sequencing and functional studies to show that CVB3 induces distinct cell-type-specific transcriptional and mitochondrial responses in human cadaveric islets. Contrary to prior claims, our analysis reveals no evidence of preferential viral tropism for β and ductal cells, instead demonstrating comparable infection rates across both endocrine and exocrine compartments. β, α, and ductal cells show the most robust transcriptional responses to infection, with ductal cells, not β cells, exhibiting the strongest interferon- and HLA-associated responses. Notably, the long non-coding MIR7-3HG modulates viral RNA expression, titer, apoptosis, and autophagy upon knockdown in stem-cell-derived islets. These findings challenge long-standing assumptions about islet-specific viral targeting and demonstrate cell-specific responses to CVB3 infection relevant to T1D.