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Cell signiling pathway of Toll-like receptor agonists with low activity

Research Project

Project/Area Number 20H03488
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 49050:Bacteriology-related
Research InstitutionSapporo Medical University

Principal Investigator

Yokota Shin-ichi  札幌医科大学, 医学部, 教授 (10325863)

Co-Investigator(Kenkyū-buntansha) 小笠原 徳子  札幌医科大学, 医学部, 講師 (00438061)
山本 聡  札幌医科大学, 医学部, 助教 (10588479)
白石 宗  札幌医科大学, 医学部, 助教 (70725168)
永島 裕之  札幌医科大学, 医学部, 研究員 (90592840)
佐藤 豊孝  札幌医科大学, 医学部, 講師 (30756474)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000)
Fiscal Year 2022: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2021: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Fiscal Year 2020: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
Keywords自然免疫 / 細菌 / リポテイコ酸 / Toll様受容体 / ミトコンドリア / クラリスロマイシン / キノロン系抗菌薬 / RSウイルス / 抗炎症 / 炎症性サイトカイン / 病原体関連分子パターン / マクロライド系抗菌薬 / 細胞内情報伝達系 / リポ多糖
Outline of Research at the Start

宿主に慢性感染、定着を成立させることのできる細菌の多くで、自然免疫応答の最前線に位置するToll様受容体(TLR)を介した細胞伝達の低下が認められている。本研究では、これら細菌におけるTLRへの認識、細胞内情報伝達系の特徴を調べることで、慢性感染、定着成立の分子機構を解明する。グラム陰性菌のリポ多糖、グラム陽性菌のリポテイコ酸と壁テイコ酸分子に着目し、それらの化学構造を明らかにして、TLRとの相互作用が高アゴニスト活性を持つ細菌のそれらとどのように異なるのかを検討し、その違いが細胞内情報伝達系に及ぼす影響について明らかにする。

Outline of Final Research Achievements

Relationship between chemical structure and biological activity of Gram-positive bacterial lipoteichoic acids as an atypical immunostimulant were determined. The diversity of fatty acid composition was found, and it related biological activity, such as induction of IL-6 in human macrophage cell lines and IgA in mouse Peyer's patch. We also found several new constituents in the lipoteichoic acids in lactic acid bacteria. Clarithromycin suppressed innate immune response by inhibition of mitochondrial function via binding to mitochondrial proteins NIPSNAP-1, 2. Many quinolone antibiotics shared not only immunomodulatory activity, but also suppression of RS virus replication via inhibition of RNA-dependent RNA polymerase.

Academic Significance and Societal Importance of the Research Achievements

自然免疫反応は感染症における宿主の初期応答として位置づけられる。本研究によって、乳酸菌群などの有用細菌の表層成分であるリポテイコ酸が免疫応答にかかわっており、その責任構造が主として脂肪酸部分にあることを示した。また、リポテイコ酸に新規の構成成分を見出すことができた。さらに、これまで抗菌薬として用いられいた薬に免疫調整機能や抗ウイルス活性を見出し、その分子機構を明らかにした。これらの知見は、従来の薬剤の新規機能の利用(drug repositioning)や新しい免疫調節剤、感染症予防治療薬開発に活用できる。

Report

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

    (10 results)

All 2023 2022 2021 Other

All Journal Article (6 results) (of which Peer Reviewed: 6 results,  Open Access: 4 results) Presentation (3 results) Remarks (1 results)

  • [Journal Article] Rapid, simple, and cost-effective plaque assay for murine norovirus using microcrystalline cellulose2023

    • Author(s)
      Yamamoto Soh、Sudo-Yokoyama Yuka、Ogasawara Noriko、Yokota Shin-ichi
    • Journal Title

      Journal of Virological Methods

      Volume: 316 Pages: 114715-114715

    • DOI

      10.1016/j.jviromet.2023.114715

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Wall teichoic acid-dependent phagocytosis of intact cell walls of Lactiplantibacillus plantarum elicits IL-12 secretion from macrophages2022

    • Author(s)
      Kojima Naoya、Kojima Shohei、Hosokawa Shin、Oda Yoshiki、Zenke Daisuke、Toura Yuta、Onohara Emi、Yokota Shin-ichi、Nagaoka Masato、Kuroda Yasuhiro
    • Journal Title

      Frontiers in Microbiology

      Volume: 13 Pages: 986396-986396

    • DOI

      10.3389/fmicb.2022.986396

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Role of Lipoteichoic Acid from the Genus <i>Apilactobacillus</i> in Inducing a Strong IgA Response2022

    • Author(s)
      Matsuzaki Chiaki、Shiraishi Tsukasa、Chiou Tai-Ying、Nakashima Yukari、Higashimura Yasuki、Yokota Shin-ichi、Yamamoto Kenji、Takahashi Tomoya
    • Journal Title

      Applied and Environmental Microbiology

      Volume: 88 Issue: 8

    • DOI

      10.1128/aem.00190-22

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Takumi-Tanimukai Y, Yamamoto S, Ogasawara N, Nakabayashi S, Mizuta K, Yamamoto K, Miyata R, Kakuki T, Jitsukawa S, Sato T, Tsutsumi H, Kojima T, Takano K, Yokota S. A hydroxypropyl methylcellulose plaque assay for human respiratory syncytial virus.2022

    • Author(s)
      Yuka Takumi-Tanimukai, Soh Yamamoto, Noriko Ogasawara, Sayaka Nakabayashi, Katsumi Mizuta, Keisuke Yamamoto, Ryo Miyata, Takuya Kakuki, Sumito Jitsukawa, Toyotaka Sato, Hiroyuki Tsutsumi, Takashi Kojima, Kenichi Takano, Shin-Ichi Yokota
    • Journal Title

      J Virol Methods

      Volume: 304 Pages: 114528-114528

    • DOI

      10.1016/j.jviromet.2022.114528

    • Related Report
      2022 Annual Research Report 2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Inhibitory Effect of the Glycerophosphate Moiety of Lipoteichoic Acid from Lactic Acid Bacteria on Dexamethasone-Induced <i>Atrogin-1</i> Expression in C2C12 Myotubes2021

    • Author(s)
      Katsuki R, Shiraishi T, Sakata S, Hirota T, Nakamura Y, Yokota S.
    • Journal Title

      Journal of Nutritional Science and Vitaminology

      Volume: 67 Issue: 5 Pages: 351-357

    • DOI

      10.3177/jnsv.67.351

    • NAID

      130008108998

    • ISSN
      0301-4800, 1881-7742
    • Year and Date
      2021-10-31
    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Oligosaccharide metabolism and lipoteichoic acid production in Lactobacillus gasseri and Lactobacillus paragasseri2021

    • Author(s)
      Shiraishi T, Maeno S, Kishi S, Fujii T, Tanno H, Hirano K, Tochio T, Tanizawa Y, Arita M, Yokota S, Endo A.
    • Journal Title

      Microorganisms

      Volume: 9 Issue: 8 Pages: 1590-1590

    • DOI

      10.3390/microorganisms9081590

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] スパルフロキサシンによるRespiratory syncytial virus複製抑制機構の解明2023

    • Author(s)
      谷向由佳、小笠原徳子、山本圭佑、横田伸一、高野賢一
    • Organizer
      第3回日本耳鼻咽喉科免疫アレルギー感染症学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Drug-repositioningによる抗RSV治療薬開発のための基礎研究2022

    • Author(s)
      谷向由佳、小笠原徳子、山本圭佑、高野賢一
    • Organizer
      第2回日本耳鼻咽喉科免疫アレルギー感染症学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Lactiplantibacillus planatrum 細胞壁の壁テイコ酸依存性のマクロファージによる貪食依存的なIL-12の産生誘導2022

    • Author(s)
      横田伸一、小島直也、小島匠平、細川伸、小田慶喜、長岡正人、黒田泰弘
    • Organizer
      第27回日本エンドトキシン・自然免疫研究会
    • Related Report
      2022 Annual Research Report
  • [Remarks] 札幌医科大学医学部微生物学講座

    • URL

      https://www.microbe-sapmed.com/

    • Related Report
      2021 Annual Research Report

URL: 

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

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