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Mechanisms of intracellular bacterial killing induced by reactive sulfur species

Research Project

Project/Area Number 19K22258
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 37:Biomolecular chemistry and related fields
Research InstitutionKumamoto University

Principal Investigator

Sawa Tomohiro  熊本大学, 大学院生命科学研究部(医), 教授 (30284756)

Co-Investigator(Kenkyū-buntansha) 津々木 博康  熊本大学, 大学院生命科学研究部(医), 助教 (40586608)
荒木 令江  熊本大学, 大学院生命科学研究部(医), 准教授 (80253722)
小野 勝彦  熊本大学, 大学院生命科学研究部(医), 助教 (80573592)
Project Period (FY) 2019-06-28 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2020: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2019: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Keywords食細胞 / 活性イオウ / 細胞内殺菌 / マクロファージ / システインパースルフィド / 食作用
Outline of Research at the Start

活性イオウとは、システインのチオール基(Cys-SH)にさらに過剰なイオウ原子が付加したシステインパースルフィド(Cys-SSH)を代表とする一連の分子である。本応募者らは、活性イオウがマクロファージによる活性酸素を抑制するにもかかわらず、細胞内殺菌を強力に高めることを見出した(未発表データ)。本研究では、活性イオウによりなぜマクロファージの細胞内殺菌力が高まるのか、その分子機構の解明を目指す。本研究の成果は、活性イオウを基軸とする新しい感染リスク群の評価、感染予防、治療法など今後益々重要となる感染症対策の構築に寄与することが期待される。

Outline of Final Research Achievements

Cysteine persulfide and polysulfides are cysteine derivatives having sulfane sulfur atoms bound to cysteine thiol. This study was conducted to clarify the impact of chemically synthesized polysulfide donors towards bacterial infections. We used N-Acetyl-L-cysteine polysulfide as potent polysulfide donors. Immune cells were infected with Salmonella enterica serovar Typhimurium LT2. Extracellular bacteria were killed by using gentamycin. NAC polysulfides were added into infected-cells during gentamycin treatment. Treatment of NAC polysulfides remarkably decreased intracellular bacterial numbers. NAC polysulfides-enhanced bacterial killing was not ascribed to increased productions of nitric oxide, cytokines, and reactive oxygen species, suggesting a non-canonical bacterium killing route. Precise understanding of mechanisms by which NAC polysulfides-mediated bacterial killing in immune cells may be helpful to develop therapeutic strategies for bacterial infectious diseases.

Academic Significance and Societal Importance of the Research Achievements

今回、活性イオウドナーの作用により、感染にともなう活性酸素を消去しながら、一方で活性酸素の殺菌作用とは全く異なる機構で細胞内の細菌を排除している可能性を強く示唆する結果を得た。今後、より積極的に活性イオウを増やすことで、特に免疫力の低下した宿主に対する新しい感染予防あるいは治療の補助方法としての展開も期待される。具体的には含硫食品(卵、緑色野菜など)の摂取や、運動によるミトコンドリア量の増加による感染予防効果の検証などが含まれる。活性イオウドナーを従来の抗菌剤と併用することでより効果的な殺菌治療への展開も期待される。

Report

(3 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • Research Products

    (10 results)

All 2021 2020 2019

All Journal Article (7 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 7 results,  Open Access: 7 results) Presentation (3 results) (of which Int'l Joint Research: 2 results,  Invited: 3 results)

  • [Journal Article] Cysteine hydropersulfide inactivates β-lactam antibiotics to form ring opened carbothioic S-acids in bacteria.2021

    • Author(s)
      Ono, K., Kitamura, Y., Zhang, T., Tsutsuki, H., Rahman, A., Akaike, T., Ihara, T., Sawa, T.
    • Journal Title

      ACS Chem Biol.

      Volume: 16 Issue: 4 Pages: 731-739

    • DOI

      10.1021/acschembio.1c00027

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [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 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Preparation of Biodegradable PLGA-Nanoparticles Used for pH-Sensitive Intracellular Delivery of an Anti-inflammatory Bacterial Toxin to Macrophages2020

    • Author(s)
      Harada Ayaka、Tsutsuki Hiroyasu、Zhang Tianli、Lee Ruda、Yahiro Kinnosuke、Sawa Tomohiro、Niidome Takuro
    • Journal Title

      Chemical and Pharmaceutical Bulletin

      Volume: 68 Issue: 4 Pages: 363-368

    • DOI

      10.1248/cpb.c19-00917

    • NAID

      130007824942

    • ISSN
      0009-2363, 1347-5223
    • Year and Date
      2020-04-01
    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Enzymatic Regulation and Biological Functions of Reactive Cysteine Persulfides and Polysulfides2020

    • Author(s)
      Sawa Tomohiro、Motohashi Hozumi、Ihara Hideshi、Akaike Takaaki
    • Journal Title

      Biomolecules

      Volume: 10 Issue: 9 Pages: 1245-1245

    • DOI

      10.3390/biom10091245

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Involvement of protein disulfide isomerase in subtilase cytotoxin-induced cell death in HeLa cells2020

    • Author(s)
      Tsutsuki Hiroyasu、Zhang Tianli、Harada Ayaka、Rahman Azizur、Ono Katsuhiko、Yahiro Kinnosuke、Niidome Takuro、Sawa Tomohiro
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 525 Issue: 4 Pages: 1068-1073

    • DOI

      10.1016/j.bbrc.2020.03.008

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Synthesis of Pegylated Manganese Protoporphyrin as a Catalase Mimic and Its Therapeutic Application to Acetaminophen-Induced Acute Liver Failure2019

    • Author(s)
      Zhang Tianli、Fang Jun、Tsutsuki Hiroyasu、Ono Katsuhiko、Islam Waliul、Sawa Tomohiro
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 42 Issue: 7 Pages: 1199-1206

    • DOI

      10.1248/bpb.b19-00152

    • NAID

      130007672166

    • ISSN
      0918-6158, 1347-5215
    • Year and Date
      2019-07-01
    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Enhanced Cellular Polysulfides Negatively Regulate TLR4 Signaling and Mitigate Lethal Endotoxin Shock2019

    • Author(s)
      Zhang Tianli、Ono Katsuhiko、Tsutsuki Hiroyasu、Ihara Hideshi、Islam Waliul、Akaike Takaaki、Sawa Tomohiro
    • Journal Title

      Cell Chemical Biology

      Volume: in press Issue: 5 Pages: 686-698.e4

    • DOI

      10.1016/j.chembiol.2019.02.003

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 活性イオウによるNLRP3インフラマソームのレドックス調節機構2020

    • Author(s)
      澤 智裕
    • Organizer
      第19回分子予防環境医学研究会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] N-Acetyl-L-cysteine polysulfides act as potent polysulfide donors and mitigate lethal endotoxin shock via their anti-inflammatory effects.2019

    • Author(s)
      Zhang, T., Ono, K., Tsutsuki, H., Ihara, H., Islam, W., Akaike, T., Sawa, T.
    • Organizer
      The 9th Biennial Meeting of Society for Free Radical Research-Asia
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] N-Acetyl-L-cystine polysulfides act as potent persulfide/polysulfide donors and ameliorate lethal endotoxin shock via their anti-inflammatory effects.2019

    • Author(s)
      Sawa, T.
    • Organizer
      1st International Conference on Persulfide and Sulfur Metabolism in Biology and Medicine
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited

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Published: 2019-07-04   Modified: 2022-01-27  

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