Enteroviruses and Type 1 Diabetes: Multiple Mechanisms and Factors?

Abstract

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by insulin deficiency and resultant hyperglycemia. Complex interactions of genetic and environmental factors trigger the onset of autoimmune mechanisms responsible for development of autoimmunity to β cell antigens and subsequent development of T1D. A potential role of virus infections has long been hypothesized, and growing evidence continues to implicate enteroviruses as the most probable triggering viruses. Recent studies have strengthened the association between enteroviruses and development of autoimmunity in T1D patients, potentially through persistent infections. Enterovirus infections may contribute to different stages of disease development. We review data from both human cohort studies and experimental research exploring the potential roles and molecular mechanisms by which enterovirus infections can impact disease outcome.

Keywords: enterovirus; islet autoimmunity; persistent infection; type 1 diabetes.

Figure 1

Staging and progression of type 1 diabetes (T1D). Multiple stages are recognized in the development of T1D that are defined by the appearance of single or multiple autoantibodies (Aabs) and by dysglycemia stages. Virus infection triggers or other environmental triggers can occur in multiple stages, and multiple triggers may be commonly required to produce the clinical onset of T1D.

Figure 2

Potential mechanisms in enterovirus-infected cells that may contribute to triggering islet autoimmunity. β cells of T1D patients have an increased expression of CAR ❶. This, in turn, may lead to increased susceptibility to enterovirus infection. Once inside the cell, enterovirus infection can lead to ER stress ❷ or miRNA dysregulation ❸. Translation of viral proteins can lead to the production of viral antigens that resemble self antigens ❹. Virus infection can also lead to the increased production of DRiPs ❺. These viral proteins and DRiPs, once degraded, can be presented in the context of MHC-I and lead to aberrant recognition by adaptive immunity ❻. The influx of immune cells also leads to production of cytokines, which may in turn lead to bystander damage to both infected and uninfected cells ❼. Abbreviations: CAR, Coxsackie adenovirus receptor; DRiP, defective ribosome product; ER, endoplasmic reticulum; EV, enterovirus; miRNA, microRNA; MHC-I, major histocompatibility complex class I; T1D, type 1 diabetes.