Coxsackievirus B Tailors the Unfolded Protein Response to Favour Viral Amplification in Pancreatic β Cells

Type 1 diabetes (T1D) is an autoimmune disease characterized by islet inflammation and progressive pancreatic beta cell destruction. The disease is triggered by a combination of genetic and environmental factors, but the mechanisms leading to the triggering of early innate and late adaptive immunity and consequent progressive pancreatic beta cell death remain unclear. The insulin-producing beta cells are active secretory cells and are thus particularly sensitive to endoplasmic reticulum (ER) stress. ER stress plays an important role in the pathologic pathway leading to autoimmunity, islet inflammation, and beta cell death. We show here that group B coxsackievirus (CVB) infection, a putative causative factor for T1D, induces a partial ER stress in rat and human beta cells. The activation of the PERK/ATF4/CHOP branch is blunted while the IRE1 alpha branch leads to increased spliced XBP1 expression and c-Jun N-terminal kinase (JNK) activation. Interestingly, JNK1 activation is essential for CVB amplification in both human and rat beta cells. Furthermore, a chemically induced ER stress preceding viral infection increases viral replication, in a process dependent on IRE1 alpha activation. Our findings show that CVB tailors the unfolded protein response in beta cells to support their replication, preferentially triggering the pro-viral IRE1 alpha/XBP1s/JNK1 pathway while blocking the pro-apoptotic PERK/ATF4/CHOP pathway. (C) 2019 The Author(s) Published by S. Karger AG, Basel