Viral Infection of Engrafted Human Islets Leads to Diabetes

Abstract

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.

A Critical Role for the Type I Interferon Receptor in Virus-Induced Autoimmune Diabetes in Rats

“…Viral infection and innate immune activation may initiate early events in β-cells and/or immune cells that ultimately lead to autoimmune attack and T1D in genetically susceptible individuals. In the long term, findings from these studies could be transitioned to diabetes models involving human islets and human immune cells (56) in which type I IFN pathways are disrupted. The current data reinforce the need for novel approaches to diabetes prevention and treatment, such as viral vaccine development (57,58) or even cytokine-modulating therapies.…”

Humanized Mouse Models of Clinical Disease

“…To begin to investigate possible mechanisms by which Coxsackie infection could trigger T1D, human islets were infected in vitro with Coxsackie virus, and it was demonstrated that the virus could directly infect human β cells, a mechanism of how the virus could detrimentally affect human β cells not previously recognized (132). When NSG mice were transplanted with human islets and infected with Coxsackie virus, almost half of the mice reverted to a hyperglycemic state and a human-specific gene expression of profiles in grafts from infected mice showed the induction of interferon signature genes, suggesting that the infected human islets may have a contributing role in their ultimate destruction by an autoimmune response (132). …”

Autoreactive T cells in type 1 diabetes

“…Along with their epidemiological associations (29,30), enterovirus infections of β cells impair insulin secretion (118), alter mRNA/miRNA expression (119,120), and induce interferon responses (121,122) that promote β cell stress, dysfunction, and apoptosis (123). Enteroviruses may also trigger autoimmunity via presentation of self-molecules in an inflammatory context (bystander activation) (124) and/or by molecular mimicry (125)(126)(127).…”