3D intestinal development and carcinogenesis by Hippo-YAP pathway

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08424
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Yamaguchi University
• Principal Investigator: MUTSUNORI SHIRAI 山口大学, 大学院医学系研究科, 教授 (20196596)
• Co-Investigator(Kenkyū-buntansha): 浅岡 洋一 山口大学, 大学院医学系研究科, 講師 (10436644) ; 清木 誠 山口大学, 大学院医学系研究科, 教授 (50226619) ; 柴田 健輔 山口大学, 大学院医学系研究科, 講師 (50529972)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: YAP / Hippo / MAIT cell / Francisella tularensis / ribD

Outline of Final Research Achievements

Pathogenic roles of the altered metabolic programs against host immunity are poorly understood. Here, we show that a pathogenic strain Francisella tularensis subsp. tularensis (FT) has five amino acid substitutions of ribD in the riboflavin (RF) synthetic pathway; ribD is a converting enzyme responsible for generating metabolites recognized by mucosal associated invariant T (MAIT) cells. Metabolites from a free-living strain Francisella tularensis subsp. novicida (FN) activated MAIT cells in a T cell receptor (TCR)-dependent manner, whereas introduction of FT-type ribD to the free-living strain FN attenuated the activity in both humans and mice. Intranasal infection mouse model showed that the FT-type ribD-expressing FN impaired Th1-type MAIT cell expansion and bacterial clearance resulting in shortened survival compared to the free-living strain FN. These results demonstrate that Francisella tularensis acquires pathogenicity by alteration of metabolic programs during evolution.

Free Research Field

感染症

Academic Significance and Societal Importance of the Research Achievements

ヒト難治性疾患の病態解明と治療戦略の開拓を目指して研究を進めることができた。また、長年にわたり難病として未解明であった野兎病菌感染症において野兎病菌が宿主の免疫を逃れる機構として代謝のリプロラミングが寄与していることが判明し、難治性感染症の解明に貢献できた。