Rationale for enteroviral vaccination and antiviral therapies in human type 1 diabetes

Abstract

In type 1 diabetes, pancreatic beta cells are destroyed by chronic autoimmune responses. The disease develops in genetically susceptible individuals, but a role for environmental factors has been postulated. Viral infections have long been considered as candidates for environmental triggers but, given the lack of evidence for an acute, widespread, cytopathic effect in the pancreas in type 1 diabetes or for a closely related temporal association of diabetes onset with such infections, a role for viruses in type 1 diabetes remains unproven. Moreover, viruses have rarely been isolated from the pancreas of individuals with type 1 diabetes, mainly (but not solely) due to the inaccessibility of the organ. Here, we review past and recent literature to evaluate the proposals that chronic, recurrent and, possibly, persistent enteroviral infections occur in pancreatic beta cells in type 1 diabetes. We also explore whether these infections may be sustained by different virus strains over time and whether multiple viral hits can occur during the natural history of type 1 diabetes. We emphasise that only a minority of beta cells appear to be infected at any given time and that enteroviruses may become replication defective, which could explain why they have been isolated from the pancreas only rarely. We argue that enteroviral infection of beta cells largely depends on the host innate and adaptive immune responses, including innate responses mounted by beta cells. Thus, we propose that viruses could play a role in type 1 diabetes on multiple levels, including in the triggering and chronic stimulation of autoimmunity and in the generation of inflammation and the promotion of beta cell dysfunction and stress, each of which might then contribute to autoimmunity, as part of a vicious circle. We conclude that studies into the effects of vaccinations and/or antiviral drugs (some of which are currently on-going) is the only means by which the role of viruses in type 1 diabetes can be finally proven or disproven.

Keywords: Antiviral therapy; Autoimmunity; Beta cells; Enterovirus; Pancreas; Prevention; Type 1 diabetes; Vaccine; Virus.

Fig. 1

Mechanisms by which viruses may impact beta cell survival/function and contribute to type 1 diabetes pathogenesis. Evidence for each of the different proposed mechanisms is presented. Genetic susceptibility to type 1 diabetes could contribute to outcome, with specific disease-associated SNPs influencing which of the viral impact mechanisms predominate in a given individual. Furthermore, there is mounting evidence that pathways could differ depending on age at type 1 diabetes onset; although each of the pathways can occur at any age, there is evidence that autoimmunity is more pronounced in individuals with a younger age at onset, whilst beta cell dysfunction is greater in individuals who are older at onset

Fig. 2

Applicability of viral vaccines and antiviral therapies to primary, secondary and tertiary prevention of type 1 diabetes, according to the disease stages described in the scientific statement of the JDRF, the Endocrine Society, and the ADA [53]. The schematic presented here is a development of the original schematic presented by Insel et al [53]. Material from this publication has been used with the permission of ADA. Copyright and all rights reserved