Enterovirus-induced gene expression profile is critical for human pancreatic islet destruction
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.
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.
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.
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.
- Enterovirus-induced gene expression profile is critical for human pancreatic islet destruction
Volume 55, Issue 12 , pp 3273-3283
- Cover Date
- Print ISSN
- Online ISSN
- Additional Links
- Interleukin 1
- Microarray analysis
- Pancreatic beta cells
- Pancreatic islets
- Tumour necrosis factor
- Type 1 diabetes
- Industry Sectors
- Author Affiliations
- 1. Intestinal Viruses Unit, National Institute for Health and Welfare (THL), P.O. Box 30, FI-00271, Helsinki, Finland
- 2. VTT Technical Research Center of Finland, Espoo, Finland
- 3. Division of Molecular Immunology, MRC National Institute for Medical Research, London, UK
- 4. Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland
- 6. Division of Clinical Immunology, Department of Oncology, Radiology, and Clinical Immunology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
- 7. Department of Surgery, University of California, Irvine, CA, USA
- 5. Diabetes Research Institute (HSR-DRI), San Raffaele Scientific Institute, Milan, Italy
- 8. Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, the Netherlands