Research on the function of bile in human norovirus entry into human intestinal organoids.

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K07153
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49060:Virology-related
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: Murakami Kosuke 国立感染症研究所, ウイルス第二部, 主任研究官 (60586973)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: ノロウイルス / オルガノイド / 胆汁 / 感染メカニズム

Outline of Final Research Achievements

Human norovirus (HuNoV) is the leading cause of gastroenteritis, however, our understanding of mechanism of HuNoV infection, especially virus entry into cells, is still limited due to the past lack of a robust in vitro cultivation system. In this study, we aimed to unveil the mechanism of HuNoV entry into cells by utilizing stem cell-derived human intestinal organoids (HIOs) and genogroup II genotype 3 (GII.3) HuNoV, which can replicate in HIOs only in the presence of bile. Our research showed that bile acids and ceramide have important roles during GII.3 replication; bile acids enhance 1) endosomal uptake, 2) endosomal acidification, and 3) ceramide levels on the apical membrane. Furthermore, we found that GII.3 exploits these bile acid-mediated cellular dynamic changes to achieve successful infection. These findings were published in PNAS in 2020.

Free Research Field

ウイルス学

Academic Significance and Societal Importance of the Research Achievements

HuNoVは大規模な食中毒事例を引き起こすことから、社会的に重要な病原体である。しかし、長らく培養系が確立されていなかったため、HuNoVの感染メカニズムに関する知見は代替ウイルスの研究による“間接的”なものであった。その中、本研究ではHIOと感染性HuNoVを用いることで、HuNoVの感染メカニズムに関する“直接的な”知見を得た。この研究成果はHuNoVに対する抗ウイルス剤を開発する上で重要なシーズと成り得る。