Enterovirus infection & type 1 diabetes: unraveling the crime scene.

Enteroviruses have been historically associated to type 1 diabetes. Definitive proof for their implication in disease development is lacking but growing evidence suggests that they could be involved in beta cell destruction either directly by killing beta cells or indirectly, by creating an exacerbated inflammatory response in the islets, capable of attracting autoreactive T cells to the "scene of crime". Epidemiological and serological studies have been associated with the appearance of islet autoimmunity and EV RNA has been detected in prospective studies. In addition, the EV capsid protein has been detected in the islets of recent onset type 1 diabetic donors, suggesting the existence of a low-grade EV infection that could become persistent. Increasing evidence in the field shows that a "viral signature" exists in type 1 diabetes and involves interferon responses that could be sustained during prolonged periods. These include the upregulation of markers like PKR, MDA5, RIG-I, MxA and HLA-I and the release of chemokines able to attract immune cells to the islets leading to insulitis. In this scenario, the hyperexpression of HLA-I molecules would promote antigen presentation to autoreactive T cells, favoring beta cell recognition and ultimately, destruction. In this review, we provide an overview of the standing evidence that implicates EVs in beta cell "murder", we investigate the timeline of events from EV entry in the cell to beta cell death and we highlight the possible accomplices that might be involved in beta cell demise. This article is protected by copyright. All rights reserved.