Enterovirus-induced gene expression profile is critical for human pancreatic islet destruction

P. Ylipaasto, T. Smura, Peddinti Gopalacharyulu, A. Paananen, Tuulikki Seppänen-Laakso, S. Kaijalainen, H. Ahlfors, O. Korsgren, J.R.T. Lakey, R. Lahesmaa, L. Piemonti, Matej Oresic, J. Galama, M. Roivainen (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

32 Citations (Scopus)

Abstract

Aims/hypothesis
Virally induced inflammatory responses, beta cell destruction and release of beta cell autoantigens may lead to autoimmune reactions culminating in type 1 diabetes. Therefore, viral capability to induce beta cell death and the nature of virus-induced immune responses are among key determinants of diabetogenic viruses. We hypothesised that enterovirus infection induces a specific gene expression pattern that results in islet destruction and that such a host response pattern is not shared among all enterovirus infections but varies between virus strains.

Methods
The changes in global gene expression and secreted cytokine profiles induced by lytic or benign enterovirus infections were studied in primary human pancreatic islet using DNA microarrays and viral strains either isolated at the clinical onset of type 1 diabetes or capable of causing a diabetes-like condition in mice.

Results
The expression of pro-inflammatory cytokine genes (IL-1-α, IL-1-β and TNF-α) that also mediate cytokine-induced beta cell dysfunction correlated with the lytic potential of a virus. Temporally increasing gene expression levels of double-stranded RNA recognition receptors, antiviral molecules, cytokines and chemokines were detected for all studied virus strains. Lytic coxsackievirus B5 (CBV-5)-DS infection also downregulated genes involved in glycolysis and insulin secretion.

Conclusions/interpretation
The results suggest a distinct, virus-strain-specific, gene expression pattern leading to pancreatic islet destruction and pro-inflammatory effects after enterovirus infection. However, neither viral replication nor cytotoxic cytokine production alone are sufficient to induce necrotic cell death. More likely the combined effect of these and possibly cellular energy depletion lie behind the enterovirus-induced necrosis of islets.
Original languageEnglish
Pages (from-to)3273-3283
Number of pages10
JournalDiabetologia
Volume55
Issue number12
DOIs
Publication statusPublished - 2012
MoE publication typeA1 Journal article-refereed

Keywords

  • Coxsackievirus
  • echovirus
  • enterovirus
  • interleukin 1
  • microarray analysis
  • pancreatic beta cells
  • pancreatic islets
  • tumour necrosis factor
  • type 1 diabetes

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    Ylipaasto, P., Smura, T., Gopalacharyulu, P., Paananen, A., Seppänen-Laakso, T., Kaijalainen, S., Ahlfors, H., Korsgren, O., Lakey, J. R. T., Lahesmaa, R., Piemonti, L., Oresic, M., Galama, J., & Roivainen, M. (2012). Enterovirus-induced gene expression profile is critical for human pancreatic islet destruction. Diabetologia, 55(12), 3273-3283. https://doi.org/10.1007/s00125-012-2713-z