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Elucidation of the in vivo proliferation mechanism of Gram-positive pathogens through host inflammatory responses

Research Project

Project/Area Number 20H03489
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 49050:Bacteriology-related
Research InstitutionAsahikawa Medical College (2021-2022)
Keio University (2020)

Principal Investigator

Hara Hideki  旭川医科大学, 医学部, 教授 (30456892)

Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000)
Fiscal Year 2022: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2020: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
Keywords感染症 / 炎症 / インフラマソーム / グラム陽性菌 / 薬剤耐性菌
Outline of Research at the Start

本研究ではグラム陽性病原菌がどのような機序で宿主インフラマソーム応答を活性化し、感染宿主内で増殖しているのか、その機構を解明することを目的とする。インフラマソーム応答は自然免疫機構の1つであるが、申請者らの研究からむしろリステリアなどの病原菌の生体内増殖を亢進することが明らかとなった。そこでリステリアがインフラマソームを活性化する機序とインフラマソーム応答により菌の生体内増殖が加速する機構を明らかにする。

Outline of Final Research Achievements

We have reported that Gram-positive pathogens such as Listeria monocytogenes and Staphylococcus aureus activate the inflammasome to promote their proliferation within the host during infection. In this study, we found that the virulence factor LLO produced by Listeria accumulates in membrane rafts that function as signal transduction sites, promoting inflammasome response through Lyn and Syk. We identified the 223rd threonine in LLO is crucial for this activity, and replacing this amino acid results in the loss of Listerial pathogenicity. From these results, it is revealed that the inflammasome plays an important role in the pathogenesis of infections such as Listeria monocytogenes, and that it is regulated by a single amino acid within LLO.

Academic Significance and Societal Importance of the Research Achievements

インフラマソーム応答は病原菌感染で活性化されるが、非病原菌はインフラマソーム受容体に対するリガンドは発現しているにも関わらず活性化できない。インフラマソームによるこの病原菌と非病原菌の識別機構は不明であったが、本研究ではリステリアが産生する病原因子に着目することで、インフラマソームの活性化には細胞内受容体に対するリガンドだけでなく、ASCの翻訳後修飾を可能とする病原因子の存在が必須であることを突き止めた。この知見はASCの翻訳後修飾を阻害することで感染病態を改善できることを意味しており、今後、特異的な阻害剤を開発することで薬剤耐性菌の治療などに応用できる可能性を秘めいている。

Report

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

    (16 results)

All 2022 2021 Other

All Int'l Joint Research (3 results) Journal Article (2 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 2 results,  Open Access: 2 results) Presentation (9 results) (of which Int'l Joint Research: 4 results,  Invited: 2 results) Book (2 results)

  • [Int'l Joint Research] ミシガン大学(米国)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] ミシガン大学(米国)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] ミシガン大学(米国)

    • Related Report
      2020 Annual Research Report
  • [Journal Article] Listeria toxin promotes phosphorylation of the inflammasome adaptor ASC through Lyn and Syk to exacerbate pathogen expansion2022

    • Author(s)
      Tanishita Yuko、Sekiya Hisateru、Inohara Naohiro、Tsuchiya Kohsuke、Mitsuyama Masao、Nunez Gabriel、Hara Hideki
    • Journal Title

      Cell Reports

      Volume: 38 Issue: 8 Pages: 110414-110414

    • DOI

      10.1016/j.celrep.2022.110414

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Gasdermin D mediates the maturation and release of IL-1α downstream of inflammasomes2021

    • Author(s)
      Tsuchiya K, Hosojima S, Hara H, Kushiyama H, Mahib M. R., Kinoshita T, Suda T
    • Journal Title

      Cell Rep.

      Volume: 34 Issue: 12 Pages: 108887-108887

    • DOI

      10.1016/j.celrep.2021.108887

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Advances in research of innate immune sensors and diseases2022

    • Author(s)
      Hara H
    • Organizer
      第51回 日本免疫学会総会国際シンポジウム
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Inflammasome-mediated exacerbation of infectious diseases and its application2022

    • Author(s)
      Hara H
    • Organizer
      第51回 日本免疫学会総会国際シンポジウム
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] インフラマソーム応答を介した感染重症化機構2022

    • Author(s)
      原 英樹、吉村 昭彦、Nunez Gabriel
    • Organizer
      第34回微生物シンポジウム
    • Related Report
      2022 Annual Research Report
  • [Presentation] Activation of inflammasomes exacerbates Gram-positive bacteria infection through IL-18 production2022

    • Author(s)
      Hara H, Yoshimura A, Nunez G
    • Organizer
      JSICR/MMCB 2022 Joint Symposium
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] LLO promotes phosphorylation of the inflammasome adaptor ASC through Lyn to exacerbate infection2022

    • Author(s)
      Hara H, Tanishita Y, Sekiya H, Nunez G, Yoshimura A
    • Organizer
      第95回日本細菌学会総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Lyn kinase signaling promotes inflammasome activation in macrophages infected with Listeria monocytogenes2021

    • Author(s)
      Hara H, Nunez G, Yoshimura A
    • Organizer
      第50回 日本免疫学会総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Molecular mechanism of inflammasome activation induced by Gram-positive bacteria infection2021

    • Author(s)
      Hara H, Tanishita Y, Sekiya H, Nunez G, Yoshimura A
    • Organizer
      第44回 日本分子生物学会年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Recognition of Gram-positive bacteria infection in macrophages through NLRP6 inflammasome2021

    • Author(s)
      Hara H, Nunez G, Yoshimura A
    • Organizer
      The 27th international symposium on molecular cell biology of macrophages
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Analysis of the mechanism by which Gram-positive bacteria activates NLRP6 inflammasome2021

    • Author(s)
      Hideki Hara, Gabriel Nunez, Akihiko Yoshimura
    • Organizer
      第94回日本細菌学会総会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Book] リウマチ科2022

    • Author(s)
      原 英樹
    • Total Pages
      120
    • Publisher
      科学評論社
    • Related Report
      2022 Annual Research Report
  • [Book] 炎症と免疫2022

    • Author(s)
      原 英樹
    • Total Pages
      110
    • Publisher
      先端医学社
    • Related Report
      2022 Annual Research Report

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

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