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Elucidation of the redox activation mechanism of enterohemorrhagic Escherichia coli toxin SubAB and the infection control

Research Project

Project/Area Number 20K08823
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54030:Infectious disease medicine-related
Research InstitutionKumamoto University

Principal Investigator

Tsutsuki Hiroyasu  熊本大学, 大学院生命科学研究部(医), 講師 (40586608)

Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords細菌毒素 / 腸管出血性大腸菌 / レドックス / 小胞体ストレス / Subtilase cytotoxin
Outline of Research at the Start

腸管出血性大腸菌(EHEC)が産生するSubtilase cytotoxin(SubAB)は、AサブユニットとBサブユニットから構成されるAB型毒素であり、EHECの重要な病原因子と考えられている。応募者は、SubABが宿主細胞に侵入し、標的分子である小胞体のBiPを切断する過程において酸化還元(レドックス)調節による活性化を受けていることを見出した。SubABはAサブユニットにジスルフィド結合をもつことが報告されており、宿主レドックス関連分子による調節がSubABの毒性に関わることが示唆される。本研究では、宿主レドックス関連分子の同定と阻害剤の探索、マウス感染モデルを用いた治療評価を行う。

Outline of Final Research Achievements

Subtilase cytotoxin (SubAB) is a toxin produced by enterohemorrhagic E. coli that exhibits endoplasmic reticulum stress-mediated cytotoxicity by cleaving the host endoplasmic reticulum chaperone protein BiP. In this study, we investigated the host redox regulators involved in SubAB toxicity and their mechanisms, and found that several host redox factors are involved in BiP cleavage by SubAB. Furthermore, by targeting these factors, he explored the inhibitory mechanism of SubAB, and found that nitric oxide, a host defense factor, exhibited inhibitory effects. This work is expected to lead to the development of new redox control strategies that can inhibit the process by which SubAB reaches the endoplasmic reticulum and cleaves BiP.

Academic Significance and Societal Importance of the Research Achievements

日本でSubAB産生EHECによる集団食中毒が起こった場合、重症化を防ぐ対策は整っていない。SubABの毒性発現機序、Stxとの相互作用や合併症(溶血性尿毒症症候群)との関連、感染病態におけるSubABの役割は不明な点が多い。一般に、EHEC感染症では、抗生剤を用いると溶菌し、菌体から大量の毒素が漏出し病態が悪化することが懸念されるため、その使用は推奨されていない。解決策として、抗生剤と併用できる毒素の阻害剤の開発が有効であると考えられる。本研究はSubABを阻害する薬剤の開発という革新的な治療戦略の構築に繋がる点で学術的的および社会的意義をもつ。

Report

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

    (22 results)

All 2023 2022 2021 2020

All Journal Article (6 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 6 results,  Open Access: 6 results) Presentation (16 results) (of which Int'l Joint Research: 2 results,  Invited: 2 results)

  • [Journal Article] Controlled Delivery of an Anti-Inflammatory Toxin to Macrophages by Mutagenesis and Nanoparticle Modification.2022

    • Author(s)
      Harada Ayaka, Tsutsuki Hiroyasu, Zhang Tianli, Yahiro Kinnosuke, Sawa Tomohiro, Niidome Takuro.
    • Journal Title

      Nanomaterials

      Volume: 12 Issue: 13 Pages: 2161-2161

    • DOI

      10.3390/nano12132161

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Non-canonical inflammasome activation analysis in a mouse model of Citrobacter rodentium infection2022

    • Author(s)
      Tsutsuki Hiroyasu、Zhang Tianli、Yahiro Kinnosuke、Toyomoto Touya、Sawa Tomohiro
    • Journal Title

      STAR Protocols

      Volume: 3 Issue: 4 Pages: 101741-101741

    • DOI

      10.1016/j.xpro.2022.101741

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Subtilase cytotoxin from Shiga-toxigenic Escherichia coli impairs the inflammasome and exacerbates enteropathogenic bacterial infection.2022

    • Author(s)
      Tsutsuki Hiroyasu, Zhang Tianli, Yahiro Kinnosuke, Ono Katsuhiko, Fujiwara Yukio, Iyoda Sunao, Wei Fan-Yan, Monde Kazuaki, Seto Kazuko, Ohnishi Makoto, Oshiumi Hiroyuki, Akaike Takaaki, Sawa Tomohiro.
    • Journal Title

      iScience

      Volume: 25 Issue: 4 Pages: 104050-104050

    • DOI

      10.1016/j.isci.2022.104050

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] New insights into the regulatory roles of glutathione in NLRP3-inflammasome-mediated immune and inflammatory responses2022

    • Author(s)
      Zhang Tianli、Tsutsuki Hiroyasu、Li Xiaoyan、Sawa Tomohiro
    • Journal Title

      The Journal of Biochemistry

      Volume: 171 Issue: 4 Pages: 367-377

    • DOI

      10.1093/jb/mvab158

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] ATP exposure stimulates glutathione efflux as a necessary switch for NLRP3 inflammasome activation.2021

    • Author(s)
      Zhang, T., Tsutsuki, H., Islam, W., Ono, K., Takeda, K., Akaike, T. and Sawa, T.
    • Journal Title

      Redox Biology

      Volume: 41 Pages: 101930-101930

    • DOI

      10.1016/j.redox.2021.101930

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Host response to the Subtilase cytotoxin produced by locus of enterocyte effacement (LEE)-negative Shiga-toxigenic Escherichia coli (STEC)2020

    • Author(s)
      Tsutsuki, H. Ogura, K. Moss, J. Yahiro, K.
    • Journal Title

      Microbiology and Immunology.

      Volume: 64 Issue: 10 Pages: 657-665

    • DOI

      10.1111/1348-0421.12841

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 腸管出血性大腸菌毒素SubABの毒性発現に関与する宿主レドックス調節の解析2023

    • Author(s)
      津々木 博康, 張 田力, 八尋 錦之助、赤池 孝章, 澤 智裕
    • Organizer
      第22回分子予防環境医学研究会大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 志賀毒素産生性大腸菌毒素SubABの毒性に関わる宿主レドックス調節機構の解明2023

    • Author(s)
      津々木 博康, 張 田力, 八尋 錦之助、赤池 孝章, 澤 智裕
    • Organizer
      第96回日本細菌学会総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Inhibitory mechanisms of enterohemorrhagic Escherichia coli toxin SubAB by nitric oxide2023

    • Author(s)
      Hiroyasu Tsutsuki, Tianli Zhang, Takaaki Akaike, Tomohiro Sawa
    • Organizer
      Nitric Oxide Gordon Research Conference
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 腸管出血性大腸菌毒素SubABの毒性発現に関わるレドックス調節機構2022

    • Author(s)
      津々木 博康, 張 田力, 八尋 錦之助、赤池 孝章, 澤 智裕
    • Organizer
      第75回日本酸化ストレス学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 腸管出血性大腸菌毒素SubABの毒性に関わる宿主レドックス調節機構2022

    • Author(s)
      津々木 博康, 張 田力, 八尋 錦之助、赤池 孝章, 澤 智裕
    • Organizer
      第33回日本生体防御学会学術総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 志賀毒素産生性大腸菌毒素SubA、Bの毒性発現に関わるレドックス調節機構2022

    • Author(s)
      津々木 博康, 張 田力, 八尋 錦之助、赤池 孝章, 澤 智裕
    • Organizer
      第68回トキシンシンポジウム
    • Related Report
      2022 Annual Research Report
  • [Presentation] Host redox regulatory mechanisms involved in the pathogenicity of enterohemorrhagic Escherichia coli toxin SubAB2022

    • Author(s)
      Hiroyasu Tsutsuki, Tianli Zhang, Kinnosuke Yahiro, Takaaki Akaike, Tomohiro Sawa
    • Organizer
      The 12th International Conference on the Biology, Chemistry, and Therapeutic Applications of Nitric Oxide. REDOX WEEK in SENDAI 2022
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 腸管出血性大腸菌毒素Subtilase cytotoxinの毒性発現に対する活性窒素種の阻害機構2022

    • Author(s)
      津々木 博康、張 田力、八尋 錦之助、赤池 孝章、澤 智裕
    • Organizer
      第21回分子予防環境医学研究会大会
    • Related Report
      2021 Research-status Report
  • [Presentation] 宿主防御機構に及ぼす志賀毒素産生性大腸菌毒素subtilase cytotoxinの影響2022

    • Author(s)
      津々木 博康、八尋 錦之助、赤池 孝章、澤 智裕
    • Organizer
      第95回日本細菌学会総会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] 腸管出血性大腸菌毒素Subtilase cytotoxinに対する活性窒素種の阻害作用2021

    • Author(s)
      津々木 博康、張 田力、八尋 錦之助、小野 勝彦、赤池 孝章、澤 智裕
    • Organizer
      第74回日本酸化ストレス学会 第21回日本NO学会合同学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] 活性窒素種による腸管出血性大腸菌毒素subtilase cytotoxin阻害機構の解析2021

    • Author(s)
      津々木 博康、張 田力、八尋 錦之助、赤池 孝章、澤 智裕
    • Organizer
      第32回日本生体防御学会学術総会
    • Related Report
      2021 Research-status Report
  • [Presentation] 志賀毒素産生性大腸菌毒素Subtilase cytotoxinに対する活性窒素種の作用機序の解明2021

    • Author(s)
      津々木博康、張田力、八尋錦之助、小野勝彦、赤池孝章、澤智裕
    • Organizer
      第67回トキシンシンポジウム
    • Related Report
      2021 Research-status Report
  • [Presentation] 腸管出血性大腸菌毒素Subtilase cytotoxinの毒性に及ぼす活性窒素種の影響2021

    • Author(s)
      津々木 博康、張 田力、八尋 錦之助、赤池 孝章、澤 智裕
    • Organizer
      第20回分子予防環境医学研究会大会
    • Related Report
      2020 Research-status Report
  • [Presentation] 一酸化窒素による腸管出血性大腸菌毒素Subtilase cytotoxinの阻害機構の解析2021

    • Author(s)
      津々木 博康、張 田力、八尋 錦之助、小野 勝彦、赤池 孝章、澤 智裕
    • Organizer
      第94回日本細菌学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] 腸管出血性大腸菌毒素Subtilase cytotoxinの細胞毒性に関わるレドックス調節機構の解析2020

    • Author(s)
      津々木 博康、張 田力、八尋 錦之助、小野 勝彦、赤池 孝章、澤 智裕
    • Organizer
      第73回日本酸化ストレス学会 第20回日本NO学会合同学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] 腸管出血性大腸菌毒素SubABによる宿主自然免疫抑制機構2020

    • Author(s)
      津々木 博康
    • Organizer
      第31回日本生体防御学会学術総会
    • Related Report
      2020 Research-status Report
    • Invited

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

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