Chronic virus infection link with diabetes
Growing evidence suggests that there is a causal association between persistent enterovirus (EV) infection and development of inflammation that ultimately leads to type 1 diabetes (T1D). The EU-funded PEVNET (Persistent virus infection as a cause of pathogenic inflammation in type 1 diabetes - An innovative research program of biobanks and expertise) project studied this potential association. Persistent EV infections are likely to be regulated by genes that modify the host's immune response against Evs. Researchers therefore performed immunohistochemistry and reverse transcription polymerase chain reaction to detect Evs in the pancreas of T1D patients. The same samples have tested positive for actively replicating the virus, thereby indicating progression of EV persistence. PEVNET scientists analysed T1D patients and controls for their innate immune responses to Evs. Varying EV strains differed in their ability to induce such responses. Mechanisms by which Evs can evade the host immune system were also identified. Coxsackievirus strains' ability to induce innate immune system responses differed, mediated by their interaction with plasmocytoid dendritic cells. An EV receptor, chimeric antigen receptor, was mainly expressed in beta cells, while being less abundant in other pancreas cell types. Analysis of the cellular infiltrate in the pancreas, coupled with identification of the molecular targets of anti-EV cytotoxic T cell responses revealed the nature and extent of pancreatic inflammation during EV infection and its impact on pancreas morphology and function. Results from genotyping samples from T1D patients, pre-diabetic subjects and control subjects suggested that genetic variants located in two distinct loci affect the course of EV infection. This may indicate a potential pathogenic mechanism leading to T1D in genetically susceptible subjects infected with Evs. Vaccination for EV-induced diabetes was analysed in animal models and in clinical treatment trials. Virus-like EV particles (VLPs) were produced and purified. A VLP-based EV vaccine was strongly immunogenic in mice, and VLPs worked well as antigens in antibody assays. An effective vaccine deployed in early childhood could prevent EV infection and T1D. Combined with antiviral agents, this approach could be delivered at low cost but with major social and economic benefits. PEVNET therefore represents a seismic step in efforts to improve the health of the population of the EU and beyond.
Keywords
Enterovirus, inflammation, type 1 diabetes, PEVNET, immune response, vaccine
