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Studies on analysis of replication system on dsRNA virus and development of its drugs

Research Project

Project/Area Number 21K05957
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 42020:Veterinary medical science-related
Research InstitutionYamaguchi University

Principal Investigator

Iwata Hiroyuki  山口大学, 共同獣医学部, 教授 (40193750)

Co-Investigator(Kenkyū-buntansha) 渋谷 周作  山口大学, 共同獣医学部, 准教授 (20534473)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Keywordsレオウイルス / ウイルス複製 / エンドサイトーシス / AMPK / 小胞体 / イバラキウイルス / オートファジー / AMPK経路 / 小胞体ストレス
Outline of Research at the Start

本研究ではdsRNAレオウイルスの複製機構の解明からの創薬探索を目的として、オルビウイルス等をモデルとして次の研究を実施する。①細胞内侵入経路としてどのエンドサイトーシス経路を利用しているか?、②エンドソームの酸性化は細胞質内への脱出に必要か?、③ウイルス増殖にオートファジー/アポトーシス経路を利用しているか?、④ウイルス複製は小胞体ストレスの影響を受けるか?の命題について検証する。ウイルス複製機構の解析に用いる各経路のインヒビターのうち、ウイルス増殖抑制効果を示すものは創薬候補となり、増殖促進するものはアンタゴニスト開発の基礎データとなる。

Outline of Final Research Achievements

In this study, we investigated a virus replication system and then novel anti-virus drugs for dsRNA reovirus using orbivirus (Ibarakivirus) as a model. In results, IBAV enters cells via endocytosis and subsequently escapes into the cytoplasm upon endosomal acidification. We found that IBAV replication was not suppressed by inhibitors of clathrin-mediated or caveolin-mediated endocytosis but was markedly suppressed by 5-(N-ethyl-N-isopropyl) amiloride (EIPA) and cytochalasin D, both of which inhibit macropinocytosis. Monensin, which inhibits endosomal acidification, also suppressed IBAV replication. Furthermore, inhibitors of mitochondrial oxidative phosphorylation, carbonyl cyanide m-chlorophenyl hydrazone (CCCP) and antimycin A suppressed IBAV propagation with reduced cellular ATP levels resulting from suppression of ATP synthesis. we identified AMP-activated protein kinase (AMPK), which is activated by CCCP or antimycin A, as a key signaling molecule in IBAV suppression.

Academic Significance and Societal Importance of the Research Achievements

本研究の目的はウイルス複製機構を解明し、診断・治療に貢献することであり、中でも研究途上にあるdsRNAウイルスについてオルビウイルスをモデルとして究明する。すなわち、ウイルス複製機構について、最新の知見に基づき、ウイルス侵入経路、エンドソームからの脱出、ウイルス粒子形成・増幅におけるアポトーシス及びオートファジーの関与、から解明することにより、各段階に有効な抗ウイルス薬を探索することを社会的意義と捉えている。ウイルス複製機構の解析には各経路のインヒビターを用いるが、ウイルス増殖抑制効果を示すものは重要な創薬候補となり、増殖促進するものはアンタゴニスト開発の基礎データとなる。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (16 results)

All 2024 2023 2022 2021 Other

All Journal Article (10 results) (of which Peer Reviewed: 10 results,  Open Access: 2 results) Presentation (5 results) Remarks (1 results)

  • [Journal Article] AMP-activated protein kinase (AMPK) suppresses Ibaraki virus propagation2024

    • Author(s)
      Ohkubo Kiichi、Shibutani Shusaku、Iwata Hiroyuki
    • Journal Title

      Virology

      Volume: 590 Pages: 109943-109943

    • DOI

      10.1016/j.virol.2023.109943

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] IgG and insulin enhance endocytosis in THP-1?cells via activation of phosphatidylinositol 3-kinase (PI3K)2023

    • Author(s)
      Egusa Karin、Shibutani Shusaku、Iwata Hiroyuki
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 679 Pages: 160-166

    • DOI

      10.1016/j.bbrc.2023.09.008

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cancer-specific apoptosis induction in canine lymphoma cell lines by the endocytosis inhibitor dynasore2023

    • Author(s)
      SUEMURA Miki、MIYATA Haruki、KAWAMURA Rio、TAKAHASHI Sho、IGASE Masaya、MIZUNO Takuya、OHAMA Takashi、SHIBUTANI Shusaku、IWATA Hiroyuki
    • Journal Title

      Journal of Veterinary Medical Science

      Volume: 85 Issue: 8 Pages: 820-827

    • DOI

      10.1292/jvms.23-0036

    • ISSN
      0916-7250, 1347-7439
    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Development of a high‐throughput screening method for the detection of 188 pathogenic variants and its application in Mishima cattle2023

    • Author(s)
      Shibutani Shusaku、Endo Mikiko、Mizukami Keijiro、Hosoi Eiji、Sakai Yusuke、Taniguchi Masayasu、Harada Hisashi、Momozawa Yukihide、Iwata Hiroyuki
    • Journal Title

      Animal Genetics

      Volume: 54 Issue: 3 Pages: 416-417

    • DOI

      10.1111/age.13301

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mechanistic/mammalian target of rapamycin complex 1 (mTORC1) signaling is involved in phagocytosis activation during THP-1 cell differentiation2023

    • Author(s)
      MUROKAWA Hiroka、EGUSA Karin、SHIBUTANI Shusaku、IWATA Hiroyuki
    • Journal Title

      Journal of Veterinary Medical Science

      Volume: 85 Issue: 7 Pages: 772-780

    • DOI

      10.1292/jvms.22-0504

    • ISSN
      0916-7250, 1347-7439
    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The endocytosis inhibitor dynasore induces a DNA damage response pathway that can be manipulated for enhanced apoptosis2023

    • Author(s)
      Suemura Miki、Shibutani Shusaku、Iwata Hiroyuki
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 645 Pages: 1-9

    • DOI

      10.1016/j.bbrc.2023.01.035

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Nuclear-targeted 4E-BP1 is dephosphorylated, induces nuclear translocation of eIF4E, and alters mRNA translation2022

    • Author(s)
      Takahashi Sho、Shibutani Shusaku、Iwata Hiroyuki
    • Journal Title

      Experimental Cell Research

      Volume: 418 Issue: 1 Pages: 113246-113246

    • DOI

      10.1016/j.yexcr.2022.113246

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Ibaraki virus enters host cells by macropinocytosis2021

    • Author(s)
      Yuki Maeda , Shusaku Shibutani , Keiko Onishi , Hiroyuki Iwata
    • Journal Title

      Virus Research

      Volume: 302 Pages: 198492-198492

    • DOI

      10.1016/j.virusres.2021.198492

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Thapsigargin suppresses alpha 1-acid glycoprotein secretion independently of N-glycosylation and ER stress2021

    • Author(s)
      Goto N, Shibutani S, Miura N, Watanabe R, Iwata H.
    • Journal Title

      Biochem Biophys Res Commun .

      Volume: 552 Pages: 30-36

    • DOI

      10.1016/j.bbrc.2021.03.017

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Partial glycosylation of the Ibaraki virus NS3 protein is sufficient to support virus propagation2021

    • Author(s)
      Yuki Maeda, Shusaku Shibutani, Hiroyuki Iwata
    • Journal Title

      Virology

      Volume: 563 Pages: 44-49

    • DOI

      10.1016/j.virol.2021.08.003

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Presentation] AMPK はイバラキウイルス感染により活性化され、ウイルス増殖を抑制する2023

    • Author(s)
      大久保 毅一、渋谷 周作、岩田 祐之
    • Organizer
      日本獣医学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] IgG および Insulin は PI3K 活性化を介して THP-1 細胞の細胞外液取り込みを増強する2023

    • Author(s)
      江草 花梨、岩田 祐之、渋谷 周作
    • Organizer
      日本獣医学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] mRNA翻訳の制御因子eIF4Eの人為的な局在操作とその影響2022

    • Author(s)
      高橋 翔、渋谷 周作、岩田 祐之
    • Organizer
      第165回日本獣医学会学術集会
    • Related Report
      2022 Research-status Report
  • [Presentation] 新規の遺伝性疾患検査法を用いた黒毛和種とホルスタイン種の解析2022

    • Author(s)
      渋谷 周作、遠藤 ミキ子、水上 圭二郎、細井 栄嗣、坂井 祐介、谷口 雅康、桃沢 幸秀、岩田 祐之
    • Organizer
      第165回日本獣医学会学術集会
    • Related Report
      2022 Research-status Report
  • [Presentation] THP-1細胞のマクロファージ様分化におけるmTORC1シグナルの関与2021

    • Author(s)
      室川 弘華, 渋谷 周作, 岩田 祐之
    • Organizer
      第164回日本獣医学会学術集会
    • Related Report
      2021 Research-status Report
  • [Remarks] 山口大学共同獣医学部 獣医衛生学研究室ホームページ

    • URL

      https://ds.cc.yamaguchi-u.ac.jp/~vethyg/

    • Related Report
      2023 Annual Research Report

URL: 

Published: 2021-04-28   Modified: 2025-01-30  

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