Article

Diabetologia

, Volume 55, Issue 12, pp 3273-3283

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

  • P. YlipaastoAffiliated withIntestinal Viruses Unit, National Institute for Health and Welfare (THL)
  • , T. SmuraAffiliated withIntestinal Viruses Unit, National Institute for Health and Welfare (THL)
  • , P. GopalacharyuluAffiliated withVTT Technical Research Center of Finland
  • , A. PaananenAffiliated withIntestinal Viruses Unit, National Institute for Health and Welfare (THL)
  • , T. Seppänen-LaaksoAffiliated withVTT Technical Research Center of Finland
  • , S. KaijalainenAffiliated withIntestinal Viruses Unit, National Institute for Health and Welfare (THL)
  • , H. AhlforsAffiliated withDivision of Molecular Immunology, MRC National Institute for Medical ResearchTurku Centre for Biotechnology, University of Turku and Åbo Akademi University
  • , O. KorsgrenAffiliated withDivision of Clinical Immunology, Department of Oncology, Radiology, and Clinical Immunology, The Rudbeck Laboratory, Uppsala University
  • , J. R. T. LakeyAffiliated withDepartment of Surgery, University of California
    • , R. LahesmaaAffiliated withTurku Centre for Biotechnology, University of Turku and Åbo Akademi University
    • , L. PiemontiAffiliated withDiabetes Research Institute (HSR-DRI), San Raffaele Scientific Institute
    • , M. OresicAffiliated withVTT Technical Research Center of Finland
    • , J. GalamaAffiliated withDepartment of Medical Microbiology, Radboud University Medical Center
    • , M. RoivainenAffiliated withIntestinal Viruses Unit, National Institute for Health and Welfare (THL) Email author 

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.

Keywords

Coxsackievirus Echovirus Enterovirus Interleukin 1 Microarray analysis Pancreatic beta cells Pancreatic islets Tumour necrosis factor Type 1 diabetes