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Molecular mechanism of the high virulence of Stx2 in enterohemorrhagic E. coli infections.

Research Project

Project/Area Number 24390035
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypePartial Multi-year Fund
Section一般
Research Field Environmental pharmacy
Research InstitutionDoshisha University

Principal Investigator

Nishikawa Kiyotaka  同志社大学, 生命医科学部, 教授 (40218128)

Project Period (FY) 2012-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000)
Fiscal Year 2015: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2014: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2013: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2012: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
KeywordsShiga toxin / 小胞輸送 / リサイクリング / 腎毒性 / exosome / ペプチド / 感染症 / 腸管出血性大腸菌 / 細胞内情報伝達 / 糖脂質
Outline of Final Research Achievements

Shiga toxin (Stx) is a major virulence factor of enterohemorrhagic E. coli (EHEC), which causes bloody diarrhea, hemorrhagic colitis, and sometimes life-threatening systemic complications, such as acute encephalopathy and hemolytic-uremic syndrome. Stx can be classified into two major subgroups, Stx1a and Stx2a. Although Stx2a is highly virulent and linked with serious human disorders when compared to Stx1a, the precise molecular mechanism by which Stx2a exerts its virulence in vivo has not been elucidated at all. In this study, we found that Stx2a, but not Stx1a, released from the target cells as its active form after being processed in the cells. Interestingly, a part of this activated Stx2a constituted an exosome-like structure. This exosome-like structure was found to cause severe renal failure, such as markedly increased urine volume, suggesting a possibility of the pathological importance of this Stx2a-specific structure in the cause of systemic complications.

Report

(5 results)
  • 2015 Annual Research Report   Final Research Report ( PDF )
  • 2014 Annual Research Report
  • 2013 Annual Research Report
  • 2012 Annual Research Report
  • Research Products

    (23 results)

All 2015 2014 2013 2012 Other

All Journal Article (2 results) (of which Peer Reviewed: 2 results,  Acknowledgement Compliant: 1 results) Presentation (20 results) (of which Int'l Joint Research: 1 results,  Invited: 3 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Identification of a wide range of motifs inhibitory to Shiga toxin by affinity-driven screening of customized divalent peptides synthesized on a membrane2015

    • Author(s)
      1) Kato M., Watanabe-Takahashi M., Shimizu E., and Nishikawa K.
    • Journal Title

      Appl. Environ. Microbiol.

      Volume: 81 Issue: 3 Pages: 1092-1100

    • DOI

      10.1128/aem.03517-14

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Identification of a peptide-based neutralizer that potently inhibits both Shiga toxins 1 and 2 by targeting specific receptor- binding regions.2013

    • Author(s)
      Watanabe-Takahashi M., Tsustuki K. (contributed equally to this article)
    • Journal Title

      Infection and Immunity

      Volume: 81 Issue: 6 Pages: 2133-2138

    • DOI

      10.1128/iai.01256-12

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Presentation] 新規小胞輸送阻害薬を用いた志賀毒素のアポトーシス死誘導活性の抑制2015

    • Author(s)
      服部 隆行、高橋 美帆、椎名 勇、大橋 愛美、旦 慎吾、西川 喜代孝、内藤 幹彦
    • Organizer
      BMB2015(第38回日本分子生物学会年会、第88回日本生化学会大会 合同大会)
    • Place of Presentation
      神戸ポートアイランド
    • Year and Date
      2015-12-01
    • Related Report
      2015 Annual Research Report
  • [Presentation] Peptide-based Stx-neutralizers of treatment of STEC infections2015

    • Author(s)
      Nishikawa, K.
    • Organizer
      Seminar Series Fall 2015, Pathology and Laboratory Medicine, Boston Univ. Sch. Med.
    • Place of Presentation
      Boston Univ. Sch. Med
    • Year and Date
      2015-09-17
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] Affinity-driven screening of customized divalent peptides synthesized on a membrane identifies a wide range of inhibitory motifs against Shiga toxin2015

    • Author(s)
      Watanabe-Takahashi M, Kato M., Shimizu E., Nishikawa K.
    • Organizer
      the 9th International Symposium on Shiga toxin (Verocytotoxin) Producing Escherichia coli Infections
    • Place of Presentation
      the Westin Boston Waterfront Hotel in Boston
    • Year and Date
      2015-09-13
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 新規小胞輸送阻害薬を用いた志賀毒素による細胞死の抑制2015

    • Author(s)
      服部隆行,高橋美帆,椎名勇,大橋愛美,旦慎吾,西川喜代孝,内藤幹彦
    • Organizer
      第19回腸管出血性大腸菌感染症研究会
    • Place of Presentation
      国立医薬品食品衛生研
    • Year and Date
      2015-07-09
    • Related Report
      2015 Annual Research Report
  • [Presentation] 異なった受容体結合部位を標的とするStx阻害薬の併用による相乗効果2015

    • Author(s)
      高橋美帆、清水英子、加藤美帆子、西川喜代孝
    • Organizer
      第88回日本細菌学会総会
    • Place of Presentation
      長良川国際会議場
    • Year and Date
      2015-03-26 – 2015-03-28
    • Related Report
      2014 Annual Research Report
  • [Presentation] AB5型細菌毒素に対する多価型ペプチド性阻害薬の開発2015

    • Author(s)
      西川喜代孝
    • Organizer
      第88回日本細菌学会総会
    • Place of Presentation
      長良川国際会議場
    • Year and Date
      2015-03-26 – 2015-03-28
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] 新規小胞輸送阻害薬による志賀毒素の細胞死誘導活性の抑制2015

    • Author(s)
      服部 隆行, 高橋 美帆, 椎名 勇、大橋 愛美、旦 慎吾、西川 喜代孝, 内藤 幹彦
    • Organizer
      日本薬学会第135回年会
    • Place of Presentation
      神戸学院大学等
    • Year and Date
      2015-03-25 – 2015-03-28
    • Related Report
      2014 Annual Research Report
  • [Presentation] 受容体結合部位特異的Stx阻害薬の組み合わせによる阻害効果の増強2014

    • Author(s)
      高橋美帆、清水英子、加藤美帆子、西川喜代孝
    • Organizer
      8) 第18回腸管出血性大腸菌感染症研究会
    • Place of Presentation
      同志社大学・寒梅館
    • Year and Date
      2014-07-15 – 2014-07-16
    • Related Report
      2014 Annual Research Report
  • [Presentation] プロテアソーム阻害薬による志賀毒素誘導性細胞死の抑制2014

    • Author(s)
      服部隆行、高橋美帆、大岡伸通、西川喜代孝、内藤幹彦
    • Organizer
      7) 第18回腸管出血性大腸菌感染症研究会
    • Place of Presentation
      同志社大学・寒梅館
    • Year and Date
      2014-07-15 – 2014-07-16
    • Related Report
      2014 Annual Research Report
  • [Presentation] プロテアソーム阻害薬によるシガトキシン誘導性アポトーシスの抑制2014

    • Author(s)
      服部隆行、大岡伸通、内藤幹彦、西川喜代孝、高橋美帆
    • Organizer
      9) 第18回日本がん分子標的治療学会学術集会
    • Place of Presentation
      仙台情報・産業プラザ
    • Year and Date
      2014-06-25 – 2014-06-27
    • Related Report
      2014 Annual Research Report
  • [Presentation] 受容体結合部位を標的とした易熱性エンテロトキシン阻害薬の開発2014

    • Author(s)
      谷川 哲也、高橋美帆、山本洋、濱端崇、西川喜代孝
    • Organizer
      第87回日本細菌学会総会
    • Place of Presentation
      タワーホール船堀
    • Related Report
      2013 Annual Research Report
  • [Presentation] 志賀毒素耐性THP-1細胞クローンの単離と解析2014

    • Author(s)
      服部 隆行, 高橋 美帆, 西川 喜代孝, 内藤 幹彦
    • Organizer
      日本薬学会第134回年会
    • Place of Presentation
      熊本大学
    • Related Report
      2013 Annual Research Report
  • [Presentation] Peptide-based Stx-neutralizers of treatment of STEC infections2013

    • Author(s)
      Nishikawa, K.
    • Organizer
      International Symposium "New trends of anti-infection strategy" on The 86^<th> Annual Meeting of Japanese Society For Microbiology
    • Place of Presentation
      千葉
    • Year and Date
      2013-03-20
    • Related Report
      2012 Annual Research Report
  • [Presentation] Inhibition of Stx-induced cell death by proteasome inhibitor2013

    • Author(s)
      Hattori, T., Takahashi, M., Ohoka, N., Nishikawa, K., Naito, M
    • Organizer
      第36回日本分子生物学会年会
    • Place of Presentation
      神戸ポートアイランド
    • Related Report
      2013 Annual Research Report
  • [Presentation] 志賀毒素の分子動力学シミュレーション2013

    • Author(s)
      尾又一実、奥村久士、森義治、西川喜代孝
    • Organizer
      第36回日本分子生物学会年会
    • Place of Presentation
      神戸ポートアイランド
    • Related Report
      2013 Annual Research Report
  • [Presentation] Molecular Dynamics Simulation of Shiga Toxin2013

    • Author(s)
      Omata K., Okumura H., Mori Y., and Nishikawa K.
    • Organizer
      CBI学会2013年大会
    • Place of Presentation
      タワーホール船堀
    • Related Report
      2013 Annual Research Report
  • [Presentation] 受容体結合部位を標的とした新規コレラ毒素阻害薬の開発2013

    • Author(s)
      山本洋、高橋美帆、濱端崇、西川喜代孝
    • Organizer
      第86回日本細菌学会総会
    • Place of Presentation
      千葉
    • Related Report
      2012 Annual Research Report
  • [Presentation] Stx阻害薬MMA-tetの作用メカニズムの解明2012

    • Author(s)
      竹中康章、高橋美帆, 西川喜代孝
    • Organizer
      第16回腸管出血性大腸菌感染症研究会
    • Place of Presentation
      秋田
    • Year and Date
      2012-07-19
    • Related Report
      2012 Annual Research Report
  • [Presentation] Peptide-based Stx-neutralizers for treatment of STEC infections.2012

    • Author(s)
      Watanabe-Takahashi, M., Tsutsuki, K., Kita, E., Nishikawa. K.
    • Organizer
      The 8^<th> International Symposium on Shiga toxin(Verocytotoxin)Producing ichia coli Infections
    • Place of Presentation
      Amsterdam, Netherland
    • Year and Date
      2012-05-09
    • Related Report
      2012 Annual Research Report
  • [Presentation] 新規腸管出血性大腸菌感染症治療薬の開発

    • Author(s)
      西川喜代孝
    • Organizer
      第63回日本薬学会近畿支部総会
    • Place of Presentation
      同志社女子大学京田辺キャンパス
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Patent(Industrial Property Rights)] Stx2阻害4価ペプチドおよびこのStx2阻害4価ペプチドを含む治療薬2013

    • Inventor(s)
      西川喜代孝、高橋美帆、三井貴瑛、山崎伸二
    • Industrial Property Rights Holder
      学校法人同志社、公立大学法人大阪府立大学
    • Industrial Property Number
      2013-013746
    • Filing Date
      2013-01-28
    • Related Report
      2012 Annual Research Report

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Published: 2012-04-24   Modified: 2019-07-29  

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