Rotavirus (RV) remains the major cause of infantile gastroenteritis worldwide, although the advent of vaccination has substantially decreased associated mortality. Recently, we observed a 15% decrease in the incidence of type 1 diabetes (T1D) in Australian 0–4-year-old children following the introduction of RV vaccination, suggesting that RV vaccination could contribute to the primary prevention of this autoimmune disease. This finding builds on our human and animal studies implicating RV in the development of T1D in genetically susceptible children.
Evidence that RV induces pancreas pathology is likely to be most relevant to a role for RV in T1D. We showed that rhesus RV infected the islets of NOD mice and other species and that human RV infected monkey islets. This was not surprising because reoviruses (which, like RVs, are members of the Reoviridae family of double-stranded [ds] RNA viruses) had been shown to infect mouse pancreatic beta cells, resulting in diabetes, and up-regulate MHC class I protein expression and induce cytopathic effects in beta cells of human islets. The effects of RV on the pancreas were striking after we orally inoculated C57Bl/6 mice at weaning with rhesus RV which is closely related to human RVs and infects mouse islets in vitro. Two phases of mild, transient hyperglycaemia were observed beginning 2 and 8 days after inoculation. In the first, widespread apoptosis of pancreatic cells was associated with decreased islet regularity, size, and insulin production , but virus was not detected in the pancreas. These effects did not occur in mice deficient for Toll-like receptor (TLR)3, which is triggered by dsRNA. By the second phase, pancreas mass and islet size had recovered, associated with widespread cellular proliferation in islets and exocrine pancreas, but many islets remained irregular. Viral antigen was then detected in the pancreas for several days, during which time it was positively correlated with mild hyperglycaemia. In summary, a single RV infection had a dramatic effect to induce apoptosis in the whole pancreas, initially TLR3 mediated, followed by regeneration with residual damage to the islets. Further investigations may reveal whether RV-induced pancreas injury can trigger islet autoimmunity on a susceptible genetic background, perhaps requiring repeated RV infections as experienced by unvaccinated children. Apart from genetic background, timing of infection may be another important factor. In NOD mice that are genetically prone to immune dysregulation, RV infection in the neonatal period prevented diabetes, whereas infection at weaning or in established diabetes had the opposite effect to accelerate diabetes development. A caveat on these studies is that findings in heterologous systems, in which the species origins of RV and pancreas differ, e.g., rhesus RV on mouse pancreas, may not necessarily extrapolate to outcomes in human infants. Overall, however, it is clear that RVs induce pancreas pathology in animal models.
The incidence of childhood T1D around the world began to increase in the second half of the last century. An interesting observation in the Australian context that may be relevant to RV as a candidate environmental factor relates to the practice of mothers “rooming-in” with their newborns. This was introduced in the 1970s and entailed mother and baby remaining together rather than separating the baby to a communal nursery at night. RV was prevalent in nurseries, and the change to rooming-in would have altered the timing of exposure to RV, delaying it until later in the first year of life when, based on NOD mouse studies . RV might promote rather than retard development of diabetes.
The article's lead author, Leonard C. Harrison, said: "Vaccination against rotavirus may have the additional benefit in some children of being a primary prevention for type 1 diabetes."
The researchers reviewed molecular evidence which showed strong similarities between the rotavirus and islet autoantibodies. The fact the rotavirus mimics autoantibodies lends itself to the hypothesis that rotavirus could trigger type 1 diabetes.
The article goes on to highlight studies which show an associated decrease in incidence of type 1 diabetes following rotavirus vaccination.
In one of the studies reviewed, there was a 41% decrease in type 1 diabetes incidence among children that were fully vaccinated against rotavirus infection. The data showed 12.2 cases of type 1 per 100,000 person years in those that were vaccinated. This compared with 20.6 cases in those unvaccinated.
The researchers are keen for further research to focus in on identifying which children are most likely to be protected by rotavirus vaccination. The team is also keen to see research identify whether rotavirus infects the human pancreas before islet autoimmunity takes hold.
The research is published in the journal PLOS Pathogens.
Rose Nor
