Figure 2.

Beta cells might fail to control enterovirus (EV) replication. EVs are able to replicate in both alpha and beta cells. Once the virus has entered the cells through its interaction with Coxsackie‐adenovirus receptor (CAR, viral RNA is sensed by protein kinase R (PKR) and melanoma differentiation‐associated protein 5 (MDA5), which induce the production of interferon (IFN)‐I and the creation of an anti‐viral state in the cell. This includes the up‐regulation of myxovirus resistance protein (MxA) (increasing IFN production) and islet human leukocyte antigen‐I (HLA‐I) expression. Due to a more efficient blocking of protein translation 8, alpha cells are able to stop viral production. In addition, IFN and other IFN‐related molecules are expressed at a higher level in alpha cells compared to beta cells, allowing them to rapidly eliminate the virus. Conversely, beta cells present a more sustained EV protein and IFN‐induced markers expression, reflecting a more chronic and non‐cytolytic infection 8. Additionally, beta cells can harbor persistent infections 11 and non‐cytopathic slow replicating viruses have been detected in the pancreas of persistently infected NOD mice 12, suggesting that beta cells might fail to control viral replication. Lastly, a sustained IFN‐stimulated HLA‐I hyperexpression could enhance beta cell antigen presentation, potentially leading to beta cell destruction by autoreactive CD8 T cells. Alpha cells are shown in red, beta cells in green, delta cells in blue, EVs in purple and CD8 T cells in brown.