Viral infection of engrafted human islets leads to diabetes
Immunology & Microbiology
Department of Medicine; Program in Molecular Medicine; Department of Quantitative Health Sciences
Medical Subject Headings
Animals; Coxsackievirus Infections; Diabetes Mellitus, Type 1; Enterovirus B, Human; Humans; Hyperglycemia; Islets of Langerhans; *Islets of Langerhans Transplantation; Mice
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.
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Citation: 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.