Type 1 diabetes genetic risk and persistent beta cell enteroviral infection - a lethal combination?

Type 1 diabetes (T1D) is an autoimmune disease that results from the selective destruction of the insulin producing beta cells in the pancreas. Treatment involves life-long, multiple daily injections of insulin to control blood sugar. Although improved by therapeutic developments, the ability to maintain blood glucose within a physiologically appropriate range in such patients remains less efficient than the normal mechanisms of homeostasis. This increases the likelihood of the development of diabetic complications, such as blindness and kidney disease, increasing the burden further on both affected individuals and the wider healthcare community. Despite many years of research we do not fully understand how and why the beta cells are attacked by the immune system, although, a combination of T1D associated genetic susceptibility and environmental triggers are believed to initiate the immune attack. Over 50 different genes have been associated with development of the disease in genome-wide association (GWA) studies with >80% of these expressed by beta cells. Ingenuity pathway analyses has revealed a strong contribution from anti-viral signalling pathways, implying a firm relationship between genetic predisposition and host anti-viral responses. Intriguingly, there is considerable epidemiological evidence implicating enteroviruses (HEVs) in the development of disease. Our group has demonstrated that rather than an acute lytic infection, a low level persistent enteroviral infection of the beta cells, occurs in the pancreas of individuals with type 1 diabetes. This correlates closely with islet hyperexpression of Class I HLA (HLA-I), a hallmark feature of affected individuals, which is believed to promote the recognition of beta cells by autoreactive cells by making them more visible to the immune system. In preliminary work, we have developed an in vitro model of a persistent enteroviral infection in a human beta cell, where low numbers of cells exhibit signs of infection, but all the cells within the culture have elevated HLA-I resembling the situation observed in vivo.

To date, most studies aiming to define the factors driving islet autoimmunity have focused on genetic and environmental factors in isolation, rather than taking a wider view in which multiple parameters are considered together. This proposal seeks to address this gap by examining the interplay between specific single nucleotide polymorphisms (SNPs) that influence the risk of developing T1D and an environmental component (enterovirus infection). We intend to target two of the genes associated with type 1 diabetes, IFIH1 and TYK2 that encode proteins involved in sensing and response to viral infections. SNPs within these genes are associated with the propensity to develop disease in GWA studies and we have selected three such SNPs that cause missense mutations leading to altered protein function/expression. These have the potential to modify the susceptibility of beta cells to infection and/or to alter their response to interferons (IFN) which may, in turn, influence the expression of HLA-I. Specifically we aim to generate human pancreatic beta cells that contain three SNP variants and will assess the impact of these on acute (early) and persistent (late) enteroviral infection using our new cell culture model. By examining the signalling pathways that are initiated under these circumstances we will identify key components that might be targeted for intervention. Ultimately, this research should aid in the development of vaccine therapies for genetically susceptible individuals. It will also facilitate the development of anti-viral treatments for autoantibody positive patients or those with recent-onset disease with a view to preventing or slowing beta cell loss in affected individuals.

Type 1 diabetes (T1D) is an autoimmune disease which results from the selective targeting of the insulin producing beta cells in the pancreas. It is thought to arise via a complex interplay between genetic, immune and environmental factors. Over 50 different genes have been associated with the disease with >80% of these expressed by beta cells. Ingenuity pathway analyses of these has revealed a firm relationship between genetic predisposition and host anti-viral responses. There is considerable evidence implicating enteroviruses (HEVs) in the development of disease and our group has demonstrated that a low level persistent HEV infection of the beta cells, occurs in the pancreas of individuals with T1D. This correlates closely with islet hyperexpression of Class I HLA (HLA-I), which is believed to promote antigen recognition by autoreactive cells. In preliminary work, we have developed an in vitro human beta cell model of a persistent HEV infection, where low numbers of cells exhibit signs of infection, but all cells have elevated HLA-I resembling the situation in vivo. In this proposal we will target two T1D associated genes, IFIH1 and TYK2 that encode proteins involved in sensing and response to viral infections. SNPs within these genes are associated with disease in genome-wide association studies and we have selected three SNPs that cause missense mutations and lead to altered protein function/expression. This proposal will examine the hypothesis that: Defined T1D risk alleles alter beta cell responsiveness to HEV infection, promoting the establishment of a low level persistent infection which triggers specific cellular responses enhancing the likelihood of antigen recognition (elevated HLA-I) and targeting by immune cells. Uniquely, this project will examine the interplay between specific single nucleotide polymorphisms (SNPs) that influence the risk of developing T1D and an environmental component (HEV infection) implicated in promoting islet autoimmunity.

This research will determine how specific genetic changes associated with the development of type 1 diabetes can impact upon the outcome of an enterovirus infection, a potential trigger of autoimmunity in susceptible individuals.
This work is likely to have a positive impact on a number of important beneficiaries that include (1) Patients with type 1 diabetes; (2) Individuals at-risk of developing type 1 diabetes; (3) the wider scientific community; (4) NHS; (5) Pharmaceutical Industry; and (6) the General Public. These are expanded briefly below.

(1 & 2) Importantly, in the longer term, this work should benefit diabetes sufferers, their families and individuals who are at high genetic risk of developing Type 1 diabetes. This condition has a significant impact on both the quality of life and life expectancy of these individuals. This research could provide a means through which the complications of disease could be slowed in affected individuals and the disease potentially prevented in the at-risk populations.

(3) The wider scientific community in the fields of type 1 diabetes, virology, immunology, pathology and other chronic diseases would benefit. This project will improve our understanding of the mechanisms through which a low level, persistent enteroviral infection can trigger autoimmunity in genetically susceptible individuals.

(4) The NHS would be a major beneficiary as the current therapies are expensive and patients require extensive management from healthcare professionals. If the complications of the disease can be reduced and/ or the disease prevented in the first place, this would significantly reduce the burden the NHS currently shoulders.

(5) The pharmacutical industry would benefit in two ways, firstly through confirmation that enteroviruses are playing a role in the development of autoimmunity in susceptible individuals, which would open up the potential to develop vaccines for the at-risk population. Secondly, our persistent enteroviral infection model system could provide a more realistic platform in which they could test the efficacy of their anti-viral therapies.

(6) We have identified several routes through which we can encourage public engagement and have a positive societal impact. These are described in more detail within the application. Engaging with diabetes support groups, charities and the general public to disseminate our research findings provides a two-way dialogue between ourselves and interested parties. This helps increase the public awareness of this condition, and encourages support for the sufferers, their families and the diabetes charities.