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

J Innate Immun. 2019;11(4):375-390. doi: 10.1159/000496034. Epub 2019 Feb 20.


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.

Keywords: Endoplasmic reticulum stress; Enterovirus; IRE1α; Type 1 diabetes; c-Jun N-terminal kinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Coxsackievirus Infections / immunology
  • Coxsackievirus Infections / metabolism*
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / metabolism*
  • Endoribonucleases / genetics
  • Endoribonucleases / metabolism
  • Enterovirus B, Human / physiology*
  • Humans
  • Immune Evasion
  • Insulin-Secreting Cells / immunology*
  • Insulin-Secreting Cells / virology
  • MAP Kinase Kinase 4 / metabolism
  • Multienzyme Complexes / genetics
  • Multienzyme Complexes / metabolism
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Rats
  • Signal Transduction
  • Unfolded Protein Response / immunology*
  • Virus Replication
  • X-Box Binding Protein 1 / genetics
  • X-Box Binding Protein 1 / metabolism


  • Ern1 protein, rat
  • Multienzyme Complexes
  • X-Box Binding Protein 1
  • Xbp1 protein, rat
  • Protein Serine-Threonine Kinases
  • MAP Kinase Kinase 4
  • Endoribonucleases