Abstract
Aims/hypothesisThe Diabetes Virus Detection (DiViD) study is the first study to laparoscopically collect pancreatic tissue and purified pancreatic islets together with duodenal mucosa, serum, peripheral blood mononuclear cells (PBMCs) and stools from six live adult patients (age 24–35 years) with newly diagnosed type 1 diabetes. The presence of enterovirus (EV) in the pancreatic islets of these patients has previously been reported.MethodsIn the present study we used reverse transcription quantitative real-time PCR (RT-qPCR) and sequencing to characterise EV genomes present in different tissues to understand the nature of infection in these individuals.ResultsAll six patients were found to be EV-positive by RT-qPCR in at least one of the tested sample types. Four patients were EV-positive in purified islet culture medium, three in PBMCs, one in duodenal biopsy and two in stool, while serum was EV-negative in all individuals. Sequencing the 5′ untranslated region of these EVs suggested that all but one belonged to enterovirus B species. One patient was EV-positive in all these sample types except for serum. Sequence analysis revealed that the virus strain present in the isolated islets of this patient was different from the strain found in other sample types. None of the islet-resident viruses could be isolated using EV-permissive cell lines.Conclusions/interpretationEV RNA can be frequently detected in various tissues of patients with type 1 diabetes. At least in some patients, the EV strain in the pancreatic islets may represent a slowly replicating persisting virus.Graphical abstract
Highlights
Type 1 diabetes is caused by the destruction of insulinproducing beta cells in the pancreas leading to insulin deficiency and lifelong dependency on daily insulin therapy
All six patients were found to be EV-positive by reverse transcription quantitative real-time PCR (RT-qPCR) in at least one of the tested sample types
Our results suggest that some individuals with type 1 diabetes are affected by a systemic EV B infection that has spread to the pancreas, as represented by patient 6 in this series
Summary
Type 1 diabetes is caused by the destruction of insulinproducing beta cells in the pancreas leading to insulin deficiency and lifelong dependency on daily insulin therapy. The small number of infected cells and low viral copy numbers found in reverse transcription quantitative real-time PCR (RT-qPCR) analysis possibly suggest a low-grade persistent-type infection in the islets Such persisting EV infection has previously been linked to chronic cardiomyopathies where the virus is characterised by deletions in its genome, low rate of replication and abnormal balance between positive- and negative-stranded viral RNA in the infected tissue [4]. EVs have a tropism to pancreatic islets and insulin-producing beta cells This has been documented in fatal EV infections, characterised by spreading of the virus to the islets where the virus causes cell damage and inflammation [5, 6]. Insulin-producing beta cells express the coxsackie and adenovirus receptor (CAR), which serves as the major receptor for coxsackievirus B (CVB) group EVs, giving one possible biological explanation to this phenomenon [8, 9]
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