Reduced Tyk2 gene expression in β-cells due to natural mutation determines susceptibility to virus-induced diabetes.

Kenichi Izumi,Yasunobu Yoshikai,Daiki Miyakawa,Yoshiyuki Niho,Koichi Akashi,Kanako Hirakawa,Hiroko Minagawa,Hironori Kurisaki,Shuji Fujimoto,Miho Teshima,Hitoshi Katsuta,Manami Hara,Keizo Anzai,Seiho Nagafuchi,Teruo Yamashita,Yuji Kai,Toshinobu Kurafuji,Hisakata Yamada,Takashi Kobayashi,Keisuke Ina,Kazuya Shimoda,Keiichiro Mine,H Ikeda ,Yūta Inoue ,Akira Inada ,Shinichiro Ogawa

doi:10.1038/ncomms7748

Abstract

Accumulating evidence suggests that viruses play an important role in the development of diabetes. Although the diabetogenic encephalomyocarditis strain D virus induces diabetes in restricted lines of inbred mice, the susceptibility genes to virus-induced diabetes have not been identified. We report here that novel Tyrosine kinase 2 (Tyk2) gene mutations are present in virus-induced diabetes-sensitive SJL and SWR mice. Mice carrying the mutant Tyk2 gene on the virus-resistant C57BL/6 background are highly sensitive to virus-induced diabetes. Tyk2 gene expression is strongly reduced in Tyk2-mutant mice, associated with low Tyk2 promoter activity, and leads to decreased expression of interferon-inducible genes, resulting in significantly compromised antiviral response. Tyk2-mutant pancreatic β-cells are unresponsive even to high dose of Type I interferon. Reversal of virus-induced diabetes could be achieved by β-cell-specific Tyk2 gene expression. Thus, reduced Tyk2 gene expression in pancreatic β-cells due to natural mutation is responsible for susceptibility to virus-induced diabetes.

Highlights

Accumulating evidence suggests that viruses play an important role in the development of diabetes
It is thought that innate immunity, such as interferon (IFN), macrophages and early inflammatory responses, most likely determines outcomes after EMC-D virus infection, since EMC-D virus-induced diabetes develops within 4 days after infection, and infection to T-lymphocyte-deficient or B-lymphocyte-deficient mice did not make the mice more susceptible to virus-induced diabetes[15,17]
We carried out intraperitoneal challenge with 1.0 Â 103 plaque-forming unit of EMC-D virus to Tyk[2] gene knockout (Tyk[2] KO) and wild-type (Tyk[2] WT) male mice with virus-induced diabetes-resistant C57BL/6J (B6) background, and measured blood glucose levels

Summary

Introduction

Accumulating evidence suggests that viruses play an important role in the development of diabetes. McCartney et al.[23] reported that MDA5 and TLR3 are both required to activate IFN-dependent antiviral responses, in preventing EMC-D virus-induced diabetes in mice. IFN receptor (IFNR)-associated molecules including Tyrosine kinase 2 (Tyk2), Janus kinase 1 (Jak1), Signal Transducers and Activator of Transcription (Stat) 1 and Stat[2] are all involved in IFNR-mediated downstream signalling, operating IFN-dependent antiviral responses (Fig. 1). These observations taken together suggest that molecules involved in innate immunity could serve as candidate genes that determine the susceptibility of sensitive strains of mice to virusinduced diabetes. The human TYK2 gene was mapped to the possible type 1 diabetes susceptibility locus[25]

Methods

Results

Conclusion