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Understanding the mechanism of infection dynamics of paramyxoviruses caused by abnormal membrane fusion and its inhibition

Research Project

Project/Area Number 20H03497
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 49060:Virology-related
Research InstitutionKyoto University

Principal Investigator

Hashiguchi Takao  京都大学, 医生物学研究所, 教授 (50632098)

Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000)
Fiscal Year 2022: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2021: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Fiscal Year 2020: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Keywords膜融合 / 構造 / エントリー / ウイルス学 / 構造生物学 / パラミクソウイルス / 神経感染
Outline of Research at the Start

ウイルスは細胞に侵入する際、細胞受容体との結合および膜融合の連鎖反応により厳密に制御されている。通常、ウイルスの細胞/組織指向性は受容体やプロテアーゼ等との相互作用に依存し、膜融合という現象自体は単にウイルス膜と細胞膜を融合させる補助的な役割と捉えられていた。しかし、我々を含む複数の研究により、膜融合能変化に伴う異常な細胞/組織指向性の獲得機構が存在することが示された。そこで、本研究では、“膜融合”をキーワードに、パラミクソウイルス感染症における異常膜融合機構の全体像を明らかにすることに取り組む。

Outline of Final Research Achievements

In this study, we analyzed the effects of changes in membrane fusion ability of paramyxoviruses such as measles virus and mumps virus on cellular/tissue tropism at the atomic, molecular, and cellular scales. The results revealed that the amino acid substitution sites responsible for the enhanced membrane fusion ability of measles virus are localized to specific structural regions of the membrane fusion protein. In addition, using the structural information to design molecules that control and inhibit membrane fusion, we successfully constructed new molecules with high infection-inhibitory activity.

Academic Significance and Societal Importance of the Research Achievements

パラミクソウイルス科は、麻疹(はしか)を起こす麻疹ウイルスや流行性耳下腺炎(おたふくかぜ)の原因であるムンプスウイルスといった臨床上重要な病原体を含む。従って、パラミクソウイルスにおける膜融合変化を通じた病原性の理解とその感染制御に関する研究を行うことは、パラミクソウイルスへの学問的な理解だけに留まらず、予防・治療法への活用を含めた感染対策として医療や福祉にも貢献が期待できる。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • Research Products

    (17 results)

All 2023 2022 2021 2020 Other

All Int'l Joint Research (2 results) Journal Article (7 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 4 results,  Open Access: 4 results) Presentation (7 results) (of which Int'l Joint Research: 4 results,  Invited: 6 results) Book (1 results)

  • [Int'l Joint Research] Icahn School of Medicine at Mount Sinai(米国)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] マウントサイナイ医科大学/ラホヤアレルギー免疫研究所(米国)

    • Related Report
      2020 Annual Research Report
  • [Journal Article] Application of Acoustic Ejection MS System to High-Throughput Screening for SARS-CoV-2 3CL Protease Inhibitors2022

    • Author(s)
      Hasegawa Tsukasa、Imamura Riyo M.、Suzuki Tateki、Hashiguchi Takao、Nomura Takao、Otsuguro Satoko、Maenaka Katsumi、Sasaki Michihito、Orba Yasuko、Sawa Hirofumi、Sato Akihiko、Okabe Takayoshi、Nagano Tetsuo、Kojima Hirotatsu
    • Journal Title

      Chemical and Pharmaceutical Bulletin

      Volume: 70 Issue: 3 Pages: 199-201

    • DOI

      10.1248/cpb.c21-01003

    • NAID

      130008165547

    • ISSN
      0009-2363, 1347-5223
    • Year and Date
      2022-03-01
    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Fitness selection of hyperfusogenic measles virus F proteins associated with neuropathogenic phenotypes2021

    • Author(s)
      Ikegame Satoshi、Hashiguchi Takao、Hung Chuan-Tien、Dobrindt Kristina、Brennand Kristen J.、Takeda Makoto、Lee Benhur
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 118 Issue: 18

    • DOI

      10.1073/pnas.2026027118

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Unique Tropism and Entry Mechanism of Mumps Virus2021

    • Author(s)
      Kubota Marie、Hashiguchi Takao
    • Journal Title

      Viruses

      Volume: 13 Issue: 9 Pages: 1746-1746

    • DOI

      10.3390/v13091746

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 構造生物学的手法による麻疹・ムンプスウイルスの細胞侵入及び侵入阻害機構の研究2021

    • Author(s)
      橋口隆生
    • Journal Title

      生体の科学

      Volume: 72 Pages: 335-338

    • Related Report
      2021 Annual Research Report
  • [Journal Article] ムンプスウイルス糖鎖受容体とその認識機構2021

    • Author(s)
      橋口隆生
    • Journal Title

      ウイルス

      Volume: 71 Pages: 185-190

    • Related Report
      2021 Annual Research Report
  • [Journal Article] Viral Biophysics: Contributions to Drug Modalities2021

    • Author(s)
      MAENAKA Katsumi、FUKUHARA Hideo、HASHIGUCHI Takao、CAAVEIRO Jose M. M.、NAGATOISHI Satoshi、KURODA Daisuke、TSUMOTO Kouhei
    • Journal Title

      Seibutsu Butsuri

      Volume: 61 Issue: 2 Pages: 082-089

    • DOI

      10.2142/biophys.61.082

    • NAID

      130008002753

    • ISSN
      0582-4052, 1347-4219
    • Related Report
      2020 Annual Research Report
    • Open Access
  • [Journal Article] Large-Scale Expression and Purification of Mumps Virus Hemagglutinin-Neuraminidase for Structural Analyses and Glycan-Binding Assays2020

    • Author(s)
      Kubota Marie、Hashiguchi Takao
    • Journal Title

      Methods Mol Biol.

      Volume: - Pages: 641-652

    • DOI

      10.1007/978-1-0716-0430-4_55

    • ISBN
      9781071604298, 9781071604304
    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Presentation] Viral pathogenesis and pharmaceutical studies for viral infectious diseases utilizing protein science2023

    • Author(s)
      Hashiguchi T
    • Organizer
      Advanced Seminar Series on Microbiology and Immunology
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] Glycan receptor and entry mechanism of mumps virus2022

    • Author(s)
      Hashiguchi T
    • Organizer
      Sialoglyco2022,
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Structural biology of human pathogenic RNA viruses2021

    • Author(s)
      Hashiguchi T
    • Organizer
      UCLA-KU seminar series
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Molecular mechanism of glycan receptor recognition by mumps virus2021

    • Author(s)
      Hashiguchi T
    • Organizer
      The 27th East Asia Joint Symposium (EAJS)
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 麻疹ウイルスによる神経感染症の分子メカニズム2021

    • Author(s)
      橋口隆生
    • Organizer
      第 25 回日本神経感染症学会総会・学術大会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Glycan receptors for mumps virus and other paramyxoviruses2020

    • Author(s)
      Hashiguchi T
    • Organizer
      2020 Society for Glycobiology Virtual Meeting
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Identify and interrogating the functional constraints that contribute to the lack of antigenic drift in paramyxoviruses.2020

    • Author(s)
      Satoshi Ikegame, Kasopefoluwa Oguntuyo, Takao Hashiguchi, Makoto Takeda, Benhur Lee
    • Organizer
      American Society for Virology (ASV) 39th Annual Meeting
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Book] 日本の感染症 (麻疹ー急性および持続感染機構からワクチンの作用機序まで)2022

    • Author(s)
      菅又昌実編 橋口隆生
    • Total Pages
      264
    • Publisher
      南山堂
    • Related Report
      2022 Annual Research Report

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Published: 2020-04-28   Modified: 2024-01-30  

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