Kaitlin A. Davis and Andrew Mehle discuss the research and context behind the new PLOS Pathogens Pearls article, “Does rotavirus turn on type 1 diabetes?”.
There is a growing appreciation that viral infections can have long lasting impacts, well after the original infection has been cleared. One example is the proposed connection between childhood infections with rotavirus and the subsequent development of type 1 diabetes. As highlighted in a PLOS Pathogens Pearls article this month, new evidence supports this correlation and suggests that vaccination against rotavirus may contribute to a global decrease in type 1 diabetes prevalence among young children. This surprising effect of vaccination could be the first example of primary prevention of type 1 diabetes, something not currently possible.
Rotavirus, a member of the Reoviridae family, is a major cause of infantile diarrheal disease worldwide, accounting for over 215,000 deaths annually. In a powerful demonstration of the positive effects of public health campaigns, mortality associated with rotavirus infection has substantially decreased since the introduction of rotavirus vaccines. Now, multiple studies have described an associated decrease in type 1 diabetes incidence following vaccination.
How might rotavirus infection be tied to the development of type 1 diabetes? Type 1 diabetes is an autoimmune condition characterized by the destruction of beta cells in the pancreas by the body’s own immune system, leading to the functional absence of insulin While there are some genetic determinants of type 1 diabetes, the precise triggers of this autoimmune disease are not fully understood. Interestingly, portions of proteins on the surface of beta cells that are recognized by T cells – the killers of the immune system – are strikingly similar to a rotavirus capsid protein called VP7. Both the beta cell protein and its viral doppelganger VP7 are able to stimulate similar T cell responses, and this response can be observed in both humans and animals following infection and vaccination. Previous studies have directly linked rotavirus infection to the production of antibodies associated with diabetes in young children, and similarly, infections in mice have been linked to pancreatic cell death and hyperglycemia. Perhaps rotavirus infection trains the immune system to accidentally target beta cells.
Rotarix [GSK] and RotaTeq [Merck] are the most routinely used rotavirus vaccines, administered in the first six months of life. These vaccines include HLA-mimic VP7 sequences and were fully introduced to communities worldwide from 2006-2008. In studies from both Australia and the United States spanning this time period, type 1 diabetes prevalence decreased coincident with vaccine introduction. In Australia, reported by Perrett, et al., the number of new cases of type 1 diabetes among children 0-4 years of age decreased by 15% following the introduction of rotavirus vaccines. Excitingly, this finding was recapitulated in an American cohort, where a 33-37% reduction in the risk of type 1 diabetes was observed following completion of a rotavirus vaccine series. Thus, if rotavirus infection is a trigger for the development of type 1 diabetes, preventing infections by vaccination would not only reduce viral disease, but have the added benefit of reducing type 1 diabetes. This is exactly what is reported in these new studies and summarized in the PLOS Pathogens Pearls article.
While trends are common between these two diverse studies, there are likely additional factors that contribute to protection. An analysis of a Finnish cohort reports that associations between rotavirus vaccination and type 1 diabetes incidence were inconclusive. This may in part be due to sample size variability between the studies, but also highlights the role of geographical and environmental differences in immunity. Rotavirus mortality and vaccine efficacy are known to vary significantly by country and environment, and similarly, factors promoting type 1 diabetes incidence are likely to be diverse. If the associations outlined in these studies hold true for multiple groups and persist as children age, these findings could outline at least one ubiquitous factor that affects type 1 diabetes development worldwide.
About the Authors
Kaitlin A. Davis received her PhD in Biology from Johns Hopkins University, under the mentorship of Dr. John T. Patton, where she studied mechanisms of rotavirus immune evasion and antagonism. She is currently a postdoctoral research associate with Andrew Mehle at the University of Wisconsin Madison studying how ADP-ribosylation of influenza virus proteins regulates viral replication processes. She also serves on the American Society for Virology executive council.
Andrew Mehle received his PhD in Virology at Harvard University training with Dr. Dana Gabuzda to study virus:host interactions during HIV infection. He continued with postdoctoral training at the University of California Berkeley in the lab of Dr. Jennifer Doudna where his focus shifted to influenza virus. He established his own lab at the University of Wisconsin Madison in 2011 (mehlelab.com), where he is currently an Associate Professor in the Department of Medical Microbiology and Immunology and holds an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund.