Abstract
Enteroviruses, specifically of the Coxsackie B virus family, have been implicated in triggering islet autoimmunity and type 1 diabetes, but their presence in pancreata of patients with diabetes has not been fully confirmed.To detect the presence of very low copies of the virus genome in tissue samples from T1D patients, we designed a panel of fluorescently labeled oligonucleotide probes, each of 17-22 nucleotides in length with a unique sequence to specifically bind to the enteroviral genome of the picornaviridae family.With these probes enteroviral RNA was detected with high sensitivity and specificity in infected cells and tissues, including in FFPE pancreas sections from patients with T1D. Detection was not impeded by variations in sample processing and storage thereby overcoming the potential limitations of fragmented RNA. Co-staining of small RNA probes in parallel with classical immunstaining enabled virus detection in a cell-specific manner and more sensitively than by viral protein.
Highlights
Type 1 diabetes (T1D) is a chronic multifaceted disorder that results from selective autoimmunemediated destruction of the insulin producing β-cells
Improvements in molecular biology subsequently broadened the panel of viruses which are implicated in causing diabetes [7, 8] and the weight of evidence suggests that coxsackieviruses [9] play a role
Enteroviruses in the pancreas were detected by immunostaining for viral protein (VP1) [17, 21], which is highly expressed under acute viral infection and diminishes in persistent infection and may not be detected under circumstances where viral replication is compromised [22]
Summary
Type 1 diabetes (T1D) is a chronic multifaceted disorder that results from selective autoimmunemediated destruction of the insulin producing β-cells. Viruses have been proposed as possible initiators of islet autoimmunity and were first implicated as long ago as the nineteenth century it was not until much later that a clear association was established between mumps and diabetes [4,5,6]. Coxsackieviruses belong to the Picornaviridiae, and are small positive-sense single stranded RNA viruses, which have been shown recently to induce a persistent, slowly-replicating infection in both myocardium and pancreas. This may result from alteration to the viral genome during the progress of infection including the generation of naturally occurring 5’-deletions [12,13,14]. Non-specific interaction of the VP1 antibody with other cellular proteins has been reported [23, 24]
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