Impaired upregulation of Stat2 gene restrictive to pancreatic β-cells is responsible for virus-induced diabetes in DBA/2 mice

• Published in: Biochemical and biophysical research communications 2020-01, Vol.521 (4), p.853-860
• Main Authors: Mine, Keiichiro, Nagafuchi, Seiho, Hatano, Shinya, Tanaka, Kenichi, Mori, Hitoe, Takahashi, Hirokazu, Anzai, Keizo, Yoshikai, Yasunobu
• Format: Article
• Language: English
• Subjects: DBA/2; Stat2; Virus-induced diabetes; β-Cell
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2019.10.193

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. •Administration of high dose type 1 IFNs failed to prevent EMC-D virus-induced diabetes in DBA/2 mice.•Innate immune response pathway was enriched in B6 β-cells post EMC-D virus infection than in DBA/2 β-cells.•The upregulation of Stat2 gene was impaired restrictive to DBA/2 β-cells following EMC-D virus infection.