Enteroviral infections in the pathogenesis of type 1 diabetes: new insights for therapeutic intervention

Abstract

The development of islet autoimmunity and type 1 diabetes has long been linked with enteroviral infection but a causal relationship has proven hard to establish. This is partly because much of the epidemiological evidence derives from studies of neutralising antibody generation in blood samples while less attention has been paid to the pancreatic beta cell as a site of infection. Nevertheless, recent studies have revealed that beta cells express specific enteroviral receptors and that they can sustain a productive enteroviral infection. Importantly, they can also mount antiviral responses which attenuate viral replication and may favour the establishment of a persistent enteroviral infection. Together, these responses combine to create the Trojan horse by which enteroviruses might precipitate islet autoimmunity.

Graphical abstract

Figure 1

A model for CVB entry into beta cells via a specific CAR isoform, CAR-SIV. Recent data demonstrate that CAR-SIV is present at high levels on insulin secretory granules. Based on its structural organization, we predict that the C-terminus (CT) of CAR-SIV faces the cytoplasmic environment and importantly, the putative `extracellular domain’ (ECD) which is required for the binding of enteroviruses, faces the granule lumen during biogenesis and maturation. This suggests that during exocytosis of insulin, the extracellular domain of CAR-SIV will be displayed on the external face of the plasma membrane and would then be available to bind to enteroviruses. During subsequent endocytosis of the granule membrane for recycling, the virus would be transported inside the cell, where it could initiate infection.

Figure 2

A model of different beta cell responses to HEV infection. Following an infection with a HEV, systemic release of interferons primes the pancreas to respond to the likelihood of a local viral infection. (a) In most individuals this will lead to the induction of an anti-viral defence program which prevents the development of a sustained and productive infection of the beta cells. The virus is cleared and the host wins the battle. (b) In some individuals (possibly neonates?) who have an impaired anti-viral defence, enterovirus enters the cells and utilises critical host factors to establish a productive, lytic, infection. This can result in the release of free virus and/or viral and beta cell specific antigens. In individuals who are genetically predisposed to T1D, this damage may trigger the activation of islet autoreactive immune cells. (c) If the host anti-viral defence program only partially inhibits viral replication, then a persistent infection might develop. Persistent infections are associated with 5′UTR deletions of the viral genome and the formation of dsRNA. dsRNA can activate host pathogen recognition receptors (PRRs) such as Mda5 (encoded by IFIH1) and stimulate an enhanced interferon signature in cells. This will, in turn, lead to the upregulation of HLAI and enhanced presentation of beta cell and viral antigens at the cell surface. In `at-risk’ individuals this might then result in destruction by auto-reactive immune cells. Virus could be disseminated to other cells via extracellular vesicles, although this remains to be determined for human beta cells.