Rotavirus Infection Accelerates Type 1 Diabetes in Mice with Established Insulitis

Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Victoria 3010, Australia.
Journal of Virology (Impact Factor: 4.44). 07/2008; 82(13):6139-49. DOI: 10.1128/JVI.00597-08
Source: PubMed


Infection modulates type 1 diabetes, a common autoimmune disease characterized by the destruction of insulin-producing islet beta cells in the pancreas. Childhood rotavirus infections have been associated with exacerbations in islet autoimmunity. Nonobese diabetic (NOD) mice develop lymphocytic islet infiltration (insulitis) and then clinical diabetes, whereas NOD8.3 TCR mice, transgenic for a T-cell receptor (TCR) specific for an important islet autoantigen, show more rapid diabetes onset. Oral infection of infant NOD mice with the monkey rotavirus strain RRV delays diabetes development. Here, the effect of RRV infection on diabetes development once insulitis is established was determined. NOD and NOD8.3 TCR mice were inoculated with RRV aged > or = 12 and 5 weeks, respectively. Diabetes onset was significantly accelerated in both models (P < 0.024), although RRV infection was asymptomatic and confined to the intestine. The degree of diabetes acceleration was related to the serum antibody titer to RRV. RRV-infected NOD mice showed a possible trend toward increased insulitis development. Infected males showed increased CD8(+) T-cell proportions in islets. Levels of beta-cell major histocompatibility complex class I expression and islet tumor necrosis factor alpha mRNA were elevated in at least one model. NOD mouse exposure to mouse rotavirus in a natural experiment also accelerated diabetes. Thus, rotavirus infection after beta-cell autoimmunity is established affects insulitis and exacerbates diabetes. A possible mechanism involves increased exposure of beta cells to immune recognition and activation of autoreactive T cells by proinflammatory cytokines. The timing of infection relative to mouse age and degree of insulitis determines whether diabetes onset is delayed, unaltered, or accelerated.

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    • "Association between rotavirus and T1D was shown by Honeyman et al. [136], who demonstrated specific seroconversion and increase in autoantibodies in T1D patients. In the experimental model, rotavirus infection caused inflammation of the insulin producing cells and induction of diabetes, which was attributed to í µí»½-cell autoimmunity [137]. The authors suggested a possible mechanism which involves increased exposure of í µí»½-cells to immune recognition and activation of autoreactive T-cells by proinflammatory cytokines. "
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    ABSTRACT: We review type 1 diabetes and host genetic components, as well as epigenetics and viruses associated with type 1 diabetes, with added emphasis on the enteroviruses, which are often associated with triggering the disease. Genus Enterovirus is classified into twelve species of which seven (Enterovirus A, Enterovirus B, Enterovirus C, and Enterovirus D and Rhinovirus A, Rhinovirus B, and Rhinovirus C) are human pathogens. These viruses are transmitted mainly by the fecal-oral route; they may also spread via the nasopharyngeal route. Enterovirus infections are highly prevalent, but these infections are usually subclinical or cause a mild flu-like illness. However, infections caused by enteroviruses can sometimes be serious, with manifestations of meningoencephalitis, paralysis, myocarditis, and in neonates a fulminant sepsis-like syndrome. These viruses are often implicated in chronic (inflammatory) diseases as chronic myocarditis, chronic pancreatitis, and type 1 diabetes. In this review we discuss the currently suggested mechanisms involved in the viral induction of type 1 diabetes. We recapitulate current basic knowledge and definitions.
    12/2014; 2014. DOI:10.1155/2014/738512
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    • "Monkey rotavirus RRV Acceleration (at 12 weeks) Graham et al. (2008) Lymphocytic choriomeningitis virus Prevention Oldstone (1990) and Filippi et al. (2009) Lactate dehydrogenase virus Prevention Takei et al. (1992) Mouse hepatitis virus Inhibition Wilberz et al. (1991) Murine gammaherpes virus-68 Delay Smith et al. (2007) Coxsackie B3 & B4 viruses Inhibition Tracy et al. (2002), Davydova et al. (2003) and Filippi et al. (2009) Coxsackie B4 virus Acceleration (at 8 weeks) Serreze et al. (2000) Viral antigens CpG DNA Inhibition Quintana et al. (2000) CpG DNA No effect Lee et al. (2005) Poly I:C Prevention Serreze et al. (1989) "
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    ABSTRACT: Type 1 diabetes is increasing dramatically in incidence in the developed world. While there may be several reasons for this, improved sanitation and public health measures have altered our interactions with certain infectious agents such as helminths. There is increasing interest in the use of helminths or their products to alleviate inflammatory or allergic conditions. Using rodent models of diabetes, it has been possible to explore the therapeutic potential of both live infections as well as helminth-derived products on the development of autoimmunity. This review provides an overview of the findings from animal models and additionally explores the potential for translation to the clinic.
    International journal for parasitology 01/2013; 43(3-4). DOI:10.1016/j.ijpara.2012.12.004 · 3.87 Impact Factor
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    • "In addition, animal models have provided evidence that the timing of rotavirus infection may be important. In NOD mice, oral infection with rotavirus accelerated the development of diabetes when insulitis was already present (26). In contrast, infection with rotavirus in young NOD mice without insulitis appears to delay the onset of type 1 diabetes (27). "
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    ABSTRACT: OBJECTIVE Type 1 diabetes is a common chronic childhood disease, and the incidence is increasing globally. Childhood infections are considered a potential environmental trigger of type 1 diabetes. Alternatively, improved hygiene and reduced childhood infections could explain the increase in type 1 diabetes in developed countries. The association of reported illnesses during infancy and later development of islet autoimmunity (IA) were examined in the Diabetes Autoimmunity Study in the Young.RESEARCH DESIGN AND METHODS Complete illness interviews through 9 months of age were collected for 1,729 children, 1,174 without a family history of type 1 diabetes, and 555 children with a first-degree relative with type 1 diabetes. Persistent IA was defined as positive antibodies to insulin, glutamic acid decarboxylase, or tyrosine phosphatase on at least two consecutive study visits.RESULTSThere were 109 children with persistent IA among the 1,729 children with illness records. A greater number of gastrointestinal illnesses were associated with an increased risk of IA, but only among children who were exposed to gluten-containing grains (wheat or barley) either <4 months of age (hazard ratio 1.37 [95% CI 1.22-1.55]; P < 0.0001) or ≥7 months of age (1.12 [1.05-1.19]; P = 0.0005) compared with 4-6 months of age (P for interaction = 0.02). There were no associations of upper respiratory symptoms, respiratory illnesses, or fevers with IA.CONCLUSIONS Specific pathogens such as enteroviruses or rotavirus may increase the risk of IA in the presence of existing inflammation induced by diet.
    Diabetes care 10/2012; 35(12). DOI:10.2337/dc12-0423 · 8.42 Impact Factor
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