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Identification of host factors that regulate host susceptibility to hepatitis B virus infection and analysis of mechanisms.

Research Project

Project/Area Number 16K19145
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Virology
Research InstitutionInstitute of Physical and Chemical Research

Principal Investigator

Tsukuda Senko  国立研究開発法人理化学研究所, 生命医科学研究センター, 研究員 (20710263)

Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
KeywordsB型肝炎 / B型肝炎ウイルス / 受容体 / NTCP / 宿主因子 / 局在制御 / ウイルス / HBV / ウィルス / 感染症
Outline of Final Research Achievements

Recent identification of NTCP as a receptor for hepatitis B virus (HBV) has facilitated the analysis of molecular mechanism of the HBV entry, however, the mechanism has not been fully understood. In this study, we aimed to identify host factors that regulate host susceptibility to HBV infection and analyze mechanisms. We identified host factors that affected on the HBV entry process through a transcriptome analysis of both HBV susceptible and non-susceptible cells. Further analysis revealed that one of the identified factors was involved in the HBV internalization into the cells through the regulation of NTCP localization in the cytosol without affecting NTCP expression. These findings will promote understanding of the mechanism of the HBV entry process after the viral attachment of its receptor.

Academic Significance and Societal Importance of the Research Achievements

B型肝炎ウイルス研究では、汎用的かつ高効率にHBV感染を許容する感染培養細胞系の改善、およびマウスモデルなどのin vivo評価系の樹立が求められている。近年HBV感染受容体としてNTCPが同定され解析が進んだが、HBV侵入過程の詳細な制御機構に関しては未だほとんど不明である。今後さらに詳細な解析が必要であるが、本研究で同定したHBVの細胞内への侵入過程を制御する宿主因子は、HBV感染の動物モデルのあるいは新たな抗HBV薬の標的となり得るため、新たな薬剤開発に寄与できると考えられる。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (21 results)

All 2019 2018 2017 2016

All Journal Article (8 results) (of which Int'l Joint Research: 7 results,  Peer Reviewed: 8 results,  Open Access: 6 results,  Acknowledgement Compliant: 1 results) Presentation (11 results) (of which Int'l Joint Research: 5 results,  Invited: 2 results) Book (2 results)

  • [Journal Article] Troglitazone Impedes the Oligomerization of Sodium Taurocholate Cotransporting Polypeptide and Entry of Hepatitis B Virus Into Hepatocytes2019

    • Author(s)
      Fukano Kento、Tsukuda Senko、Oshima Mizuki、Suzuki Ryosuke、Aizaki Hideki、Ohki Mio、Park Sam-Yong、Muramatsu Masamichi、Wakita Takaji、Sureau Camille、Ogasawara Yuki、Watashi Koichi
    • Journal Title

      Frontiers in Microbiology

      Volume: 9 Pages: 3257-3257

    • DOI

      10.3389/fmicb.2018.03257

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Concept of Viral Inhibitors via NTCP.2019

    • Author(s)
      1)Tsukuda S, Fukano K, Watashi K, Wakita T.
    • Journal Title

      Semin Liver Dis.

      Volume: 39 Issue: 01 Pages: 78-95

    • DOI

      10.1055/s-0038-1676804

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A Single Adaptive Mutation in Sodium Taurocholate Cotransporting Polypeptide Induced by Hepadnaviruses Determines Virus Species Specificity2018

    • Author(s)
      Takeuchi Junko S.、Fukano Kento、Iwamoto Masashi、Tsukuda Senko、Suzuki Ryosuke、Aizaki Hideki、Muramatsu Masamichi、Wakita Takaji、Sureau Camille、Watashi Koichi
    • Journal Title

      Journal of Virology

      Volume: 93 Issue: 5 Pages: 04132-18

    • DOI

      10.1128/jvi.01432-18

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] A new strategy to identify hepatitis B virus entry inhibitors by AlphaScreen technology targeting the envelope-receptor interaction.2018

    • Author(s)
      Saso W, Tsukuda S, Ohashi H, Fukano K, Morishita R, Matsunaga S, Ohki M, Ryo A, Park SY, Suzuki R, Aizaki H, Muramatsu M, Sureau C, Wakita T, Matano T, Watashi K.
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 印刷中 Issue: 2 Pages: 374-379

    • DOI

      10.1016/j.bbrc.2018.04.187

    • Related Report
      2018 Annual Research Report 2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Chemical array system, a platform to identify novel hepatitis B virus entry inhibitors targeting sodium taurocholate cotransporting polypeptide2018

    • Author(s)
      Kaneko M, Futamura Y, Tsukuda S, Kondoh Y, Sekine T, Hirano H, Fukano K, Ohashi H, Saso W, Morishita R, Matsunaga S, Kawai F, Ryo A, Park S-Y, Suzuki R, Aizaki H, Ohtani N, Sureau C, Wakita T, Osada H, Watashi K
    • Journal Title

      Scientific Reports

      Volume: 8 Issue: 1 Pages: 2769-2769

    • DOI

      10.1038/s41598-018-20987-w

    • Related Report
      2018 Annual Research Report 2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cyclosporin derivatives inhibit hepatitis B virus entry without interfering with NTCP transporter activity.2017

    • Author(s)
      Shimura S, Watashi K, Fukano K, Peel M, Sluder A, Kawai F, Iwamoto M, Tsukuda S, Takeuchi S J, Miyake T, Sugiyama M, Ogasawara Y, Park SY, Tanaka Y, Kusuhara H, Mizokami M, Sureau C, Wakita T
    • Journal Title

      J Hepatol

      Volume: 66 Issue: 4 Pages: 685-692

    • DOI

      10.1016/j.jhep.2016.11.009

    • Related Report
      2017 Research-status Report 2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A new class of hepatitis B and D virus entry inhibitors, proanthocyanidin and its analogs, that directly act on the viral large surface proteins.2017

    • Author(s)
      Tsukuda S, Watashi K, Hojima T, Isogawa M, Iwamoto M, Omagari K, Suzuki R, Aizaki H, Kojima S, Sugiyama M, Saito A, Tanaka Y, Mizokami M, Sureau C, Wakita T
    • Journal Title

      Hepatology

      Volume: 65 Issue: 4 Pages: 1104-1116

    • DOI

      10.1002/hep.28952

    • Related Report
      2017 Research-status Report 2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Fungus-Derived Neoechinulin B as a Novel Antagonist of Liver X Receptor, Identified by Chemical Genetics Using a Hepatitis C Virus Cell Culture System2016

    • Author(s)
      Nakajima S, Watashi K, Ohashi H, Kamisuki S, Izaguirre-Carbonell J, Kwon AT, Suzuki H, Kataoka M, Tsukuda S, Okada M, Moi ML, Takeuchi T, Arita M, Suzuki R, Aizaki H, Kato T, Suzuki T, Hasegawa H, Takasaki T, Sugawara F, Wakita T
    • Journal Title

      J Virol

      Volume: 90(20) Issue: 20 Pages: 9058-74

    • DOI

      10.1128/jvi.00856-16

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Presentation] Oligomerization of NTCP induces hepatitis B virus internalization,2018

    • Author(s)
      Kento Fukano, Senko Tsukuda, Mio Ohki, Sam-Yong Park, Ryosuke Suzuki, Hideki Aizaki, Masamichi Muramatsu, Takaji Wakita, Yuki Ogasawara, Koichi Watashi,
    • Organizer
      International HBV Meeting
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 感染培養系を用いたHBV創薬と侵入機構の解析2017

    • Author(s)
      九十田千子
    • Organizer
      第13回肝免疫・ウイルス・フロンティア(Liver2017)
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] B型肝炎ウイルスを標的とするproanthocyanidinの同定と作用機序の解析2017

    • Author(s)
      九十田千子、小嶋聡一、脇田隆字
    • Organizer
      第53回日本肝臓学会総会
    • Related Report
      2017 Research-status Report
  • [Presentation] 1.Identification of a new class of HBV and HDV entry inhibitor, proanthocyanidin2017

    • Author(s)
      Tsukuda S, Watashi K, Kojima S, Wakita T
    • Organizer
      AASLD The Liver Meeting
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] NTCPを利用したHBV創薬研究およびNTCPを介したHBV侵入機構の解析2017

    • Author(s)
      九十田千子, 渡士幸一, 小嶋聡一, 脇田隆字
    • Organizer
      生命科学系学会合同年次大会 (ConBio2017)
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] Characterization of origomeric flavonoids as a novel class of anti-HBV entry inhibitors that directly target viral envelope protein.2016

    • Author(s)
      Tsukuda S, Watashi K, Hojima T, Isogawa M, Iwamoto M, Suzuki R, Aizaki H, Kojima S, Sugiyama M, Saito A, Tanaka Y, Mizokami M, Wakita T
    • Organizer
      第64回日本ウイルス学術集会
    • Place of Presentation
      札幌コンベンションセンター
    • Year and Date
      2016-10-23
    • Related Report
      2016 Research-status Report
  • [Presentation] Retinoid inhibitors abolish the host permissiveness to hepatitis B virus infection by modulating the expression of NTCP2016

    • Author(s)
      Tsukuda S, Watashi K, Iwamoto M, Suzuki R, Aizaki H, Kojima S, Sugiyama M, Saito A, Tanaka Y, Mizokami M, Wakita T
    • Organizer
      23rd International Symposium on Hepatitis C Virus and Related Viruses
    • Place of Presentation
      Kyoto International Conference Center
    • Year and Date
      2016-10-11
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Proanthocyanidin and its analogs are new class of HBV and HDV entry inhibitors that target the viral preS1 region2016

    • Author(s)
      Tsukuda S, Watashi K, Hojima T, Isogawa M, Iwamoto M, Suzuki R, Aizaki H, Kojima S, Sugiyama M, Saito A, Tanaka Y, Mizokami M, Wakita T
    • Organizer
      International meeting on molecular biology of hepatitis B viruses
    • Place of Presentation
      Yonsei University
    • Year and Date
      2016-09-21
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] B型肝炎ウイルスを標的とした新規侵入阻害剤の同定と作用機序の解析2016

    • Author(s)
      九十田千子, 小嶋聡一, 脇田隆字
    • Organizer
      第52回日本肝臓学会総会
    • Place of Presentation
      ニューホテルオータニ幕張/東京ベイ幕張ホテル
    • Year and Date
      2016-05-19
    • Related Report
      2016 Research-status Report
  • [Presentation] B型肝炎ウイルス粒子を直接標的とする侵入阻害剤proanthocyanidin2016

    • Author(s)
      九十田千子、渡士幸一、濱田義知、齊藤安貴子、五十川正記、田中義正、鈴木亮介、相崎英樹、小嶋聡一、杉山真也、田中靖人、溝上雅史、脇田隆字.
    • Organizer
      第26回抗ウイルス療法学会総会
    • Place of Presentation
      名古屋東急ホテル、名古屋市立大学
    • Year and Date
      2016-05-13
    • Related Report
      2016 Research-status Report
  • [Presentation] Inhibition of HBV entry process through targeting host and viral molecules2016

    • Author(s)
      Tsukuda S, Watashi K, Hamada Y, Isogawa M, Iwamoto M, Suzuki R, Aizaki H, Kojima S, Sugiyama M, Saito A, Tanaka Y, Mizokami M, Wakita T.
    • Organizer
      4th Taiwan-Korea-Japan Research Symposium on Hepatitis B Virus
    • Place of Presentation
      Humanities and Social Sciences Building, Taiwan
    • Year and Date
      2016-04-09
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Book] Encyclopedia of Signaling Molecules Second Edition -NTCP-2017

    • Author(s)
      Senko TsukudaMasashi IwamotoKoichi Watashi
    • Publisher
      Springer, Cham
    • ISBN
      9783319671987
    • Related Report
      2017 Research-status Report
  • [Book] Encyclopedia of Signaling Molecules, 2nd Edition2017

    • Author(s)
      Tsukuda S, Iwamoto M, Watashi K
    • Total Pages
      4700
    • Publisher
      Springer Nature
    • Related Report
      2016 Research-status Report

URL: 

Published: 2016-04-21   Modified: 2020-03-30  

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