Viral infection of engrafted human islets leads to diabetes
Immunology & Microbiology
Department of Medicine; Program in Molecular Medicine; Department of Quantitative Health Sciences
Endocrine System | Endocrine System Diseases | Immunology and Infectious Disease | Molecular Genetics
Type 1 diabetes (T1D) is characterized by the destruction of the insulin-producing beta-cells of pancreatic islets. Genetic and environmental factors both contribute to T1D development. Viral infection with enteroviruses is a suspected trigger for T1D, but a causal role remains unproven and controversial. Studies in animals are problematic because of species-specific differences in host cell susceptibility and immune responses to candidate viral pathogens such as coxsackievirus B (CVB). In order to resolve the controversial role of viruses in human T1D, we developed a viral infection model in immunodeficient mice bearing human islet grafts. Hyperglycemia was induced in mice by specific ablation of native beta-cells. Human islets, which are naturally susceptible to CVB infection, were transplanted to restore normoglycemia. Transplanted mice were infected with CVB4 and monitored for hyperglycemia. Forty-seven percent of CVB4-infected mice developed hyperglycemia. Human islet grafts from infected mice contained viral RNA, expressed viral protein, and had reduced insulin levels compared with grafts from uninfected mice. Human-specific gene expression profiles in grafts from infected mice revealed the induction of multiple interferon-stimulated genes. Thus, human islets can become severely dysfunctional with diminished insulin production after CVB infection of beta-cells, resulting in diabetes. long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
DOI of Published Version
Diabetes. 2015 Apr;64(4):1358-69. doi: 10.2337/db14-1020. Epub 2014 Nov 12. Link to article on publisher's site
Gallagher, Glen R.; Brehm, Michael A.; Finberg, Robert W.; Barton, Bruce A.; Shultz, Leonard D.; Greiner, Dale L.; Bortell, Rita; and Wang, Jennifer P., "Viral infection of engrafted human islets leads to diabetes" (2015). GSBS Student Publications. 1888.