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

Research Project

Project/Area Number 18K07153
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 49060:Virology-related
Research InstitutionNational 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
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywordsノロウイルス / オルガノイド / 胆汁 / 感染メカニズム / 胆汁酸
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.

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。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (16 results)

All 2020 2019 2018 Other

All Int'l Joint Research (3 results) Journal Article (2 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 2 results,  Open Access: 1 results) Presentation (8 results) (of which Int'l Joint Research: 5 results) Book (2 results) Remarks (1 results)

  • [Int'l Joint Research] Baylor College of Medicine(米国)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] Baylor College of Medicine(米国)

    • Related Report
      2019 Research-status Report
  • [Int'l Joint Research] Baylor College of Medicine(米国)

    • Related Report
      2018 Research-status Report
  • [Journal Article] Bile acids and ceramide overcome the entry restriction for GII.3 human norovirus replication in human intestinal enteroids2020

    • Author(s)
      Murakami Kosuke、Tenge Victoria R.、Karandikar Umesh C.、Lin Shih-Ching、Ramani Sasirekha、Ettayebi Khalil、Crawford Sue E.、Zeng Xi-Lei、Neill Frederick H.、Ayyar B. Vijayalakshmi、Katayama Kazuhiko、Graham David Y.、Bieberich Erhard、Atmar Robert L.、Estes Mary K.
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 117 Issue: 3 Pages: 1700-1710

    • DOI

      10.1073/pnas.1910138117

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Human Norovirus Cultivation in Nontransformed Stem Cell-Derived Human Intestinal Enteroid Cultures: Success and Challenges2019

    • Author(s)
      Estes Mary K.、Ettayebi Khalil、Tenge Victoria R.、Murakami Kosuke、Karandikar Umesh、Lin Shih-Ching、Ayyar B. Vijayalakshmi、Cortes-Penfield Nicolas W.、Haga Kei、Neill Frederick H.、Opekun Antone R.、Broughman James R.、Zeng Xi-Lei、Blutt Sarah E.、Crawford Sue E.、Ramani Sasirekha、Graham David Y.、Atmar Robert L.
    • Journal Title

      Viruses

      Volume: 11 Issue: 7 Pages: 638-638

    • DOI

      10.3390/v11070638

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] GII.3 human norovirus hijacks bile acid-driven cellular dynamic changes to entry human intestinal enteroids.2020

    • Author(s)
      Murakami K, Tenge VR, Karandikar U, Lin SC, Ramani S, Ettayebi K, Crawford SE, Zeng XL, Neill FH, Ayyar BV, Atmar RL and Estes MK.
    • Organizer
      American Society for Virology 39th Annual Meeting.
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Evaluating Antiviral Agents for Human Noroviruses Using a Human Intestinal Enteroid Model.2020

    • Author(s)
      Lewis MA, Cortes-Penfield NW, Tenge VR, Murakami K, Ettayebi K, Ayyar BV, Neill FH, Ramani S, Estes MK, Atmar RL.
    • Organizer
      American Society for Virology 39th Annual Meeting.
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] GII.3 human norovirus hijacks bile acid-driven cellular dynamic changes to entry human intestinal enteroids.2020

    • Author(s)
      Murakami K, Tenge VR, Karandikar U, Lin SC, Ramani S, Ettayebi K, Crawford SE, Zeng XL, Neill FH, Ayyar BV, Atmar RL and Estes MK.
    • Organizer
      Virtual ASV Calicivirus & Astrovirus Workshop Presentation.
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 胆汁酸により誘発される細胞内ダイナミクス変化を用いてGII.3ヒトノロウイルスは小腸オルガノイドに侵入する2020

    • Author(s)
      村上耕介、片山和彦
    • Organizer
      第61回日本臨床ウイルス学会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Bile acids and ceramide are critical to allow GII.3 human norovirus entry into human intestinal enteroids2019

    • Author(s)
      Murakami K., Tenge VR., Karandikar U., Lin SC., Ramani S., Ayyar BV., Atmar RL., Estes KM.
    • Organizer
      7th International Calicivirus Conference
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] 小腸オルガノイドにおける胆汁要求性ヒトノロウイルスGII.3の複製機序の解析2019

    • Author(s)
      村上 耕介、片山 和彦
    • Organizer
      第60回日本臨床ウイルス学会
    • Related Report
      2019 Research-status Report
  • [Presentation] Evaluation of the bile-driven replication of GII.3 human norovirus in human intestinal enteroids2018

    • Author(s)
      Kosuke Murakami, Victoria R. Tenge, Umesh Karandikar, Sasirekha Ramani, Khalil Ettayebi, Sue E. Crawford, Xi-Lei Zeng, Frederick H. Neill, Robert L. Atmar and Mary K. Estes
    • Organizer
      American Society for Virology
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 胆汁要求性GII.3ヒトノロウイルスのヒト小腸エンテロイドにおける複製メカニズムの解析2018

    • Author(s)
      Kosuke Murakami, Victoria R. Tenge, Umesh Karandikar, Sasirekha Ramani, Khalil Ettayebi, Xi-Lei Zeng, Sue E. Crawford, Kazuhiko Katayama, Robert L. Atmar, Mary K. Estes
    • Organizer
      第66回日本ウイルス学会学術集会
    • Related Report
      2018 Research-status Report
  • [Book] アグリバイオ 2020年5月号2020

    • Author(s)
      山﨑 毅(分担執筆:村上耕介)
    • Total Pages
      82
    • Publisher
      北隆館
    • Related Report
      2020 Annual Research Report
  • [Book] 実験医学別冊 決定版 オルガノイド実験スタンダード2019

    • Author(s)
      佐藤 俊朗、武部 貴則、永樂 元次
    • Total Pages
      372
    • Publisher
      羊土社
    • ISBN
      9784758122399
    • Related Report
      2018 Research-status Report
  • [Remarks] AMED 成果情報 ノロウイルスの細胞への侵入が胆汁酸により助長されることを発見

    • URL

      https://www.amed.go.jp/news/seika/kenkyu/20200128.html

    • Related Report
      2019 Research-status Report

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Published: 2018-04-23   Modified: 2022-01-27  

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