Molecular pathological analysis of infectious disease development using gain-of-function STAT1 knock-in mice.

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K10112
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Hiroshima University
• Principal Investigator: Tsumura Miyuki 広島大学, 医系科学研究科(医), 研究員 (80646274)
• Co-Investigator(Kenkyū-buntansha): 岡田 賢 広島大学, 医系科学研究科(医), 教授 (80457241)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: Stat1ノックインマウス / 慢性皮膚粘膜カンジダ症 / STAT1機能獲得型変異

Outline of Final Research Achievements

Patients with gain-of-function (GOF)-STAT1 mutations display a broad variety of infectious and autoimmune manifestations in addition to chronic mucocutaneous candidiasis (CMC), and those with severe infections and/or autoimmunity have a poor prognosis. In this study, we generated GOF-Stat1R274Q mice to better understand the disease pathogenesis caused by GOF-STAT1 mutations in humans. The mice replicated the human molecular and cellular phenotypes by presenting with hyperphosphorylation of STAT1 upon cytokine stimulation and impairment of Th17 cells in the small intestine. Moreover, GOF-Stat1R274Q mice might show slightly increased susceptibility to C. albicans infection, probably because of impaired IL-17-based immunity. The GOF-Stat1R274Q mice established here should be a useful model to understand the human primary immunodeficiency disease caused by GOF-STAT1 mutations.

Free Research Field

免疫不全

Academic Significance and Societal Importance of the Research Achievements

本研究ではGOF-Stat1R274QマウスでのC. albicans排除障害にTh17分化障害が重要な役割を果たすとともに、今回樹立したGOF-Stat1R274QマウスはTh17免疫応答を中心とした、CMCDの病態解明に有用であることを示した。今後は本症で多彩な感染症を発症する病態を更に解明するために、GOF-Stat1R274Qマウスを用いて、C. albicans以外の病原体としてマイコバクテリアやヘルペスなどの感染実験を行うことが必要であると考えられる。それによって、本症患者のさらなる病態解明が進むとともに、新規の治療法の開発につながることが期待される。