Viral infection of engrafted human islets leads to diabetes.
Type 1 diabetes (T1D) is characterized by the destruction of the insulin-producing β-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 β-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 β-cells, resulting in diabetes.
Department of Medicine, University of Massachusetts Medical School, Worcester, MA.
Glen R
GR
Gallagher
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA.
Michael A
MA
Brehm
Department of Medicine, University of Massachusetts Medical School, Worcester, MA.
Robert W
RW
Finberg
Department of Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA.
Bruce A
BA
Barton
The Jackson Laboratory, Bar Harbor, ME.
Leonard D
LD
Shultz
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA.
Dale L
DL
Greiner
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA.
Rita
R
Bortell
Department of Medicine, University of Massachusetts Medical School, Worcester, MA jennifer.wang@umassmed.edu.
Jennifer P
JP
Wang
D000818:Animals; D003384:Coxsackievirus Infections / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000821:virology*; D029822:Enterovirus B, Human; D006801:Humans; D006943:Hyperglycemia / Q000276:immunology / Q000821:virology*; D007515:Islets of Langerhans / Q000276:immunology / Q000821:virology*; D016381:Islets of Langerhans Transplantation; D051379:Mice