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Diabetes. 2016 Apr;65(4):996-1003. doi: 10.2337/db15-0956. Epub 2015 Nov 11.

Coxsackievirus B5 Infection Induces Dysregulation of microRNAs Predicted to Target Known Type 1 Diabetes Risk Genes in Human Pancreatic Islets.

Author information

1
Faculty of Medicine, University of New South Wales, Sydney, Australia School of Women's and Children's Health, University of New South Wales, Sydney, Australia Prince of Wales Hospital, Virology Research Laboratory, Sydney, Australia.
2
Faculty of Medicine, University of New South Wales, Sydney, Australia Prince of Wales Hospital, Virology Research Laboratory, Sydney, Australia.
3
NHMRC Clinical Trials Centre, The University of Sydney, Camperdown, Sydney, Australia.
4
St Vincent's Institute of Medical Research, Melbourne, Australia Department of Medicine, St Vincent's Hospital, The University of Melbourne, Melbourne, Australia.
5
Faculty of Medicine, University of New South Wales, Sydney, Australia Prince of Wales Hospital, Virology Research Laboratory, Sydney, Australia School of Medical Sciences, University of New South Wales, Sydney, Australia School of Biotechnology and Biomolecular Science, Faculty of Science, University of New South Wales, Sydney, Australia.
6
Faculty of Medicine, University of New South Wales, Sydney, Australia School of Women's and Children's Health, University of New South Wales, Sydney, Australia Prince of Wales Hospital, Virology Research Laboratory, Sydney, Australia Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, Australia Discipline of Pediatrics and Child Health, The Children's Hospital at Westmead Clinical School, The University of Sydney, Sydney, Australia m.craig@unsw.edu.au.

Abstract

Extensive research has identified enterovirus (EV) infections as key environmental triggers of type 1 diabetes. However, the underlying molecular mechanisms via which EVs contribute to the pathogenesis of type 1 diabetes remain unclear. Given that EVs dysregulate host microRNAs (miRNAs), which function as key regulators of β-cell biology, we investigated the impact of coxsackievirus B5 (CVB5) infection on the cellular expression of miRNAs within human islets. Using high-throughput quantitative PCR nanofluidics arrays, the expression of 754 miRNAs was examined in CVB5-infected human pancreatic islets. In total, 33 miRNAs were significantly dysregulated (≥ threefold difference) in the infected compared with control islets (P < 0.05). Subsequently, these differentially expressed miRNAs were predicted to target mRNAs of 57 known type 1 diabetes risk genes that collectively mediate various biological processes, including the regulation of cell proliferation, cytokine production, the innate immune response, and apoptosis. In conclusion, we report the first global miRNA expression profiling of CVB5-infected human pancreatic islets. We propose that EVs disrupt the miRNA-directed suppression of proinflammatory factors within β-cells, thereby resulting in an exacerbated antiviral immune response that promotes β-cell destruction and eventual type 1 diabetes.

PMID:
26558682
DOI:
10.2337/db15-0956
[Indexed for MEDLINE]
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