Mechanism of inhibition of Shiga-toxigenic Escherichia coli SubAB cytotoxicity by steroids and diacylglycerol analogues
| Project/Area Number |
16K08770
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Bacteriology (including mycology)
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| Research Institution | Chiba University |
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Principal Investigator |
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| Research Collaborator |
OGURA Kohei
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | ドラッグリポジショニング / 小胞体ストレス / 細胞死 / ステロイド / PKC活性化剤 / アポトーシス / ER ストレス / ドラッグリポジションニング / 細菌毒素 / 腸管オルガノイド / 阻害剤 / 腸管出血性大腸菌 / 毒素 |
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| Outline of Final Research Achievements |
Shiga toxigenic Escherichia coli (STEC) are responsible for a worldwide foodborne disease, which is characterized by severe bloody diarrhea and hemolytic uremic syndrome. Subtilase cytotoxin (SubAB) is a novel AB5 toxin, which is produced by LEE-negative STEC. Cleavage of the BiP protein by SubAB induces endoplasmic reticulum stress, followed by induction of cytotoxicity in vitro or lethal severe hemorrhagic inflammation in mice. Here we found that steroids and diacylglycerol (DAG) analogues inhibited SubAB cytotoxicity. Steroid-induced Bcl-xL expression was a key step in the inhibition of SubAB cytotoxicity. Bcl-xL knockdown increased SubAB-induced apoptosis in steroid-treated HeLa cells, whereas SubAB-induced cytotoxicity was suppressed in Bcl-xL overexpressing cells. While, DAG analogues suppressed SubAB activity independent of Bcl-xL expression at early time points. We show the mechanism by which steroids and DAG analogues protect cells against SubAB produced by LEE-negative STEC.
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| Academic Significance and Societal Importance of the Research Achievements |
病原細菌を対象にした感染症治療は、抗生剤を用いたものが多く、耐性菌の出現は今日でも大きな治療上の問題となっている。EHECは抗生剤による溶菌は強毒な毒素の放出が伴うなどの問題も多い。我々はドラッグリポジショニングにより、Stx2，SubABの細胞毒性を阻害する薬剤の検索を行い、その毒素阻害機構の解析を行った。本手法は、既に他の病態で利用されている薬剤に、抗毒素活性がある可能性を示唆する物である。本研究によって、毒素の細胞内侵入・輸送・致死機構を特異的に阻害する薬剤の基本構造、作用が理解されれば、有効な薬剤の構造を基本として、より効果の高い、副作用の低い薬剤の開発・臨床応用の立案に役立つ。
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Report
(4 results)
Research Products
(19 results)
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[Journal Article] Helicobacter pylori Vacuolating Cytotoxin A Causes Anorexia and Anxiety via 1 Hypothalamic Urocortin 1 in Mice2019
Author(s)
H. Suzuki, K. Ataka, A. Asakawa, K, Cheng. M, Ushikai. H. Iwai, T. Arai, K. Yahiro, K. Yamamoto, Y. Yokoyama, M. Kojima, T. Yada, T. Hirayama, N. Nakamura, A. Inu
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Journal Title
Scientific Reports
Volume: -
Related Report
Peer Reviewed / Open Access
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[Presentation] Mechanism of inhibition of Shiga-toxigenic Escherichia coli SubAB cytotoxicity by steroids and diacylglycerol analogues2019
Author(s)
Yahiro, K., S. Nagasawa, K. Ichimura, H. Takeuchi, K. Ogura, H. Tsutsuki, T. Shimizu, S. Iyoda, T. Shimizu, M. Ohnishi, H. Iwase, and M. Noda.
Organizer
U.S.-Japan Cooperative Medical Sciences Program (USJCMSP) 21st International Conference on Emerging Infectious Diseases in the Pacific Rim(Cholera and Other Bacterial Enteric Infections Panel Meeting)
Related Report
Int'l Joint Research
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