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

Abstract

Type 1 diabetes (T1D) is an autoimmune disease characterized by islet inflammation and progressive pancreatic β 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 β cell death remain unclear. The insulin-producing β 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 β 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 β cells. The activation of the PERK/ATF4/CHOP branch is blunted while the IRE1α 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 β cells. Furthermore, a chemically induced ER stress preceding viral infection increases viral replication, in a process dependent on IRE1α activation. Our findings show that CVB tailors the unfolded protein response in β cells to support their replication, preferentially triggering the pro-viral IRE1α/XBP1s/JNK1 pathway while blocking the pro-apoptotic PERK/ATF4/CHOP pathway.

Coxsackievirus B Persistence Modifies the Proteome and the Secretome of Pancreatic Ductal Cells

“…ER stress is often induced by viral infections, including CVB infections (Colli et al., 2019, Zhang et al., 2010). The type of these responses can vary depending on the cell type and the virus.…”

Presumption of innocence for beta cells: why are they vulnerable autoimmune targets in type 1 diabetes?

“…Similarly, environmental cues, such as islet-tropic CVB infections, which are candidate environmental triggers for type 1 diabetes, may synergise with ER stress when stochastically coming together in time and space. Of note, recent findings suggest that CVBs use the UPR pathway IRE1α/XBP1s/JNK1 to foster their own replication in beta cells [17]. Further indirect support for the role of ER stress and environmental factors such as CVBs come from the observation that neighbouring alpha cells are spared by islet autoimmunity.…”

Type 1 Diabetes: Interferons and the Aftermath of Pancreatic Beta-Cell Enteroviral Infection

“…Several viruses (including hepatitis C and hepatitis B viruses, Japanese encephalitis virus and human cytomegalovirus) can activate both UPR and the IRE1α/XBP1 pathway to facilitate their own replication [ 104 ]. In addition, a recent study revealed that CVB5 infection triggers the PERK and IRE1α branches of UPR in EndoC-βH1 and in the rat beta cell line, INS-1E [ 105 ]. Following CVB5 infection, a fully activated IRE1α/XBP1s pathway promoted phosphorylation and activation of JNK1, leading to an increase in viral replication and, ultimately, apoptosis.…”

“…Following CVB5 infection, a fully activated IRE1α/XBP1s pathway promoted phosphorylation and activation of JNK1, leading to an increase in viral replication and, ultimately, apoptosis. Conversely, siRNA mediated IRE1α knockdown or chemical inhibition of JNK1 reduced both responses [ 105 ]. Importantly, the pro-apoptotic and virus-activating effects of JNK1 were regulated independently.…”

“…These findings suggest that IRE1α-induced JNK1 activation may be required for efficient CVB replication in pancreatic beta cells. The same study also showed that despite activation of the PERK pathway in virally infected cells, none of the downstream ER stress markers—CHOP, ATF4 and ATF3—were induced, suggesting an incomplete activation of this branch of the UPR [ 105 ]. Enteroviruses depend on internal ribosome entry sites (IRES) to mediate protein translation and replication, and it has been shown that eIF2α is also required for IRES-dependent translation initiation [ 106 ].…”