Elucidation of the redox activation mechanism of enterohemorrhagic Escherichia coli toxin SubAB and the infection control
Project/Area Number |
20K08823
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 54030:Infectious disease medicine-related
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Research Institution | Kumamoto University |
Principal Investigator |
Tsutsuki Hiroyasu 熊本大学, 大学院生命科学研究部(医), 講師 (40586608)
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Project Period (FY) |
2020-04-01 – 2023-03-31
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Project Status |
Completed (Fiscal Year 2022)
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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)
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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。
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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.
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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。
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Report
(4 results)
Research Products
(22 results)
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[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.
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Journal Title
iScience
Volume: 25
Issue: 4
Pages: 104050-104050
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[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.
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Journal Title
Redox Biology
Volume: 41
Pages: 101930-101930
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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