Rotavirus Infection Accelerates Type 1 Diabetes in Mice with Established Insulitis

Abstract

Infection modulates type 1 diabetes, a common autoimmune disease characterized by the destruction of insulin-producing islet ␤ 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 >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 ␤-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 ␤-cell autoimmunity is established affects insulitis and exacerbates diabetes. A possible mechanism involves increased exposure of ␤ 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.

Lessons from the mouse: potential contribution of bystander lymphocyte activation by viruses to human type 1 diabetes

“…Bystander activation might occur independently of pancreatic infection and instead contribute to T cell activation in the PLN [33]. These findings could help explain why virus modulation of diabetes is not always associated with virus presence in the pancreas, and can depend on mouse age at infection [7,16,36]. The requirement for pre-existing autoreactive cells also suggests that bystander activation accelerates disease progression rather than initiating beta cell damage.…”

“…Infection of older NOD mice with established insulitis with the rotavirus strain RRV accelerates diabetes onset [7]. This acceleration is dependent on the presence of insulitis, as diabetes development is delayed or unaffected following RRV infection of infant and young adult NOD mice [98].…”

“…Viruses are considered to be key potential diabetes modulators. For example, infection by members of the Enterovirus genus of the Picornaviridae family, or the Rotavirus genus in the Sedoreovirinae subfamily of the Reoviridae family, has been associated with altered diabetes development in humans and mice [5][6][7][8]. However, a direct causal relationship between a specific environmental stimulus and diabetes onset has proven difficult to establish.…”

“…This acceleration is dependent on the presence of insulitis, as diabetes development is delayed or unaffected following RRV infection of infant and young adult NOD mice [98]. Diabetes acceleration by RRV is associated with a minimal degree of intestinal inflammation and is independent of pancreatic infection [7,29]. Instead, it involves virus spread to the MLN and PLN, where virus associates with antigen presenting cells, including DCs, inducing cellular maturation [99].…”

Shared genetics in coeliac disease and other immune-mediated diseases

“…In CD, for example, it has been suggested that rotavirus infections can increase the risk of disease [7]. Rotaviruses have also been associated with exacerbation of pancreatic islet autoimmunity in humans and shown to promote insulitis and exacerbate diabetes in NOD mice [71]. HCV has also been associated with CD, CrD and thyroiditis [70,72].…”