Abstract
Viral infection is a putative causal factor for the development of type 1 diabetes, but the exact pathogenic mechanism of virus-induced diabetes (VID) remains unclear. Here, to identify the critical factors that regulate VID, we analyzed encephalomyocarditis D (EMC-D) VID-sensitive DBA/2 mice in comparison with resistant B6 mice. EMC-D virus-induced cell death occurred more frequently in DBA/2 β-cells than in B6 β-cells with 100U/ml IFN-β priming in vitro. We therefore purified β-cells using flow cytometry from mice two days after EMC-D virus infection and subjected them to microarray analysis. As a results, innate immune response pathway was found to be enriched in B6 β-cells. The signal transducer and activator of transcription 2 (Stat2) gene interacted with genes in the pathway. Stat2 gene expression levels were lower in DBA/2 mice than in B6 mice, restrictive to β-cells. Moreover, administration of IFN-β failed to upregulate Stat2 gene in DBA/2 β-cells than in those of B6 in vivo. The viral titer significantly increased only in the DBA/2 pancreas. Thus, these provided data suggest that impaired upregulation of Stat2 gene restrictive to β-cells at the early stage of infection is responsible for VID development in DBA/2 mice.
Highlights
Type 1 diabetes (T1D) is caused by insulin-producing pancreatic b-cell destruction, usually leading to absolute insulin deficiency [1].The number of T1D is increasing annually by approximately 3% [1,2]
signal transducer and activator of transcription 2 (Stat2) gene expression levels were comparable between DBA/2 and B6 mice before infection in any organs, at two days after infection, the levels were significantly reduced specific to DBA/2 bcells (Fig. 4E,H)
It is suggests that Stat2 gene expression in b-cells is regulated by cell type-specific and viral infection condition-associated regulatory mechanisms
Summary
The number of T1D is increasing annually by approximately 3% [1,2]. Genetic factors have been widely reported as risk or protection factors for T1D; these risk factors cannot fully explain why the number of T1D cases has been increasing globally. The causal mechanisms for the increase in T1D prevalence remain unclear but may be due to changes in environmental risk factors and/ or viral infections [2]. Enterovirus-associated VP1 antigen and enterovirus RNA are often detected in pancreatic islets, and an increase in anti-enterovirus antibodies has been observed in blood from T1D patients [3e5]. Fulminant T1D, a clinical phenotype of T1D with abrupt onset, strongly suggests a viral contribution to the etiology [6]
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