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Molecular mechanism of biological activity expressed by hemolysins derived from Listeriae inside macrophages.

Research Project

Project/Area Number 14370092
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Bacteriology (including Mycology)
Research InstitutionKyoto University

Principal Investigator

MITSUYAMA Masao  Kyoto University, Graduate School of Medicine, Department of Microbiology, Professor, 医学研究科, 教授 (10117260)

Project Period (FY) 2002 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥12,600,000 (Direct Cost: ¥12,600,000)
Fiscal Year 2004: ¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2003: ¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 2002: ¥5,000,000 (Direct Cost: ¥5,000,000)
KeywordsListeria / hemolysin / macrophage / cytokine / TLR / リステリア / リステリオリシン / エスケープ / 病原性 / 細胞内寄生菌 / リコンビナント蛋白 / PEST配列
Research Abstract

On the molecular mechanisms of biological activity expressed by hemolysins derived from various Listeria spp., the following results have been obtained by using recombinant proteins and mutant strains. (1)All the hemolysin proteins, LLO, ILO and LSO, consist of 4 domains and the known hemolytic activity is highly dependent on domain 4, while the newly found cytokine-inducing activity is exclusively dependent on domain 1-3 at he N-terminus. (2)The very low cytokine-inducing activity observed in ILO appeared to be due to the absence of PEST-like sequence at the N-terminus portion. (3)Upon stimulation with LLO, macrophage first produce IL-12 and IL-18, then these IFN-γ-inducing cytokines stimulate NK cells to produce a massive amount of IFN-γ. (4)TLRs, especially TLR2 and TLR4 are both required for the cytokine production by macrophages in response to LLO. (5)The cytokine response in epithelial cells that do not express surface TLRs appeared to be due to the cytokine induction triggered by the Ca-influx caused by sublethal level of membrane damage by LLO. (6)The in-flame deletion mutant of hly (a gene encoding LLO) has been established. By using recombinant strains, it was confirmed that both escape of bacteria from phagosome into cytosolic space in macrophages and the presence of PEST-like sequence are required for cytokine response. (7)Upon infection of macrophages by Listeria monocytogenes, a significant level of upregulation was induced in hly and orfA gene expression. Oxygen radicals produced by infected macrophages appeared to be responsible for this upregulation of virulence gene expression.

Report

(4 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • Research Products

    (63 results)

All 2005 2004 2003 2002 Other

All Journal Article (37 results) Book (12 results) Publications (14 results)

  • [Journal Article] Enhanced resistance to Gram-positive bacterium and increased susceptibility to bacterial endotoxin in mice sensitized with Propionibacterium. acnes : Involvement of Toll-like receptor.2005

    • Author(s)
      Mochizuki, H.
    • Journal Title

      FEMS Immunol.Med.Microbiol. 43

      Pages: 287-293

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Listeriolysin O-induced membrane permeation mediates persistent IL-6 production in Caco-2 cells during Listeria monocytogenes infection in vitro.2005

    • Author(s)
      Tsuchiya, K.
    • Journal Title

      Infect.Immun. 73(in press)

      Pages: 1-9

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Involvement of reactive oxygen intermediate in the enhanced expression of virulence-associated genes of Listeria monocytogenes inside activated macrophages.2005

    • Author(s)
      Makino, M.
    • Journal Title

      Microbiol.Immunol. 49(in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] 自然・獲得免疫と疾患 リステリア感染2005

    • Author(s)
      光山正雄
    • Journal Title

      最新医学 60S

      Pages: 216-226

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Listeriolysin O-induced membrane permeation mediates persistent IL-6 production in Caco-2 cells during Listeria monocytogenes infection in vitro.2005

    • Author(s)
      Tsuchiya, K.
    • Journal Title

      Infect.Immun. 73 (in press)

      Pages: 1-9

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Involvement of reactive oxygen intermediate in the enhanced expression of virulence-associated genes of Listeria monocytogenes inside activated macrophages2005

    • Author(s)
      Makino, M.
    • Journal Title

      Microbiol.Immunol. (accepted)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Listerial infection : innate and acquired immunity. (a review in Japanese)2005

    • Author(s)
      Mitsuyama, M.
    • Journal Title

      Saishin-Igaku (modern Medicine) 60S

      Pages: 216-226

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Enhanced resistance to Gram-positive bacterium and increased susceptibility to bacteria lendotoxin in mice sensitized with Propionibacterium. Acens : Involvement of Toll-like receptor.2005

    • Author(s)
      Hirofumi Mochizuki
    • Journal Title

      FEMS Immunology and Medical Microbiology 43(2)

      Pages: 287-293

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Listeriolysin O-induced membrane permeation mediates persistent IL-6 production in Caco-2 cells during Listeria monocytogenes infection in vitro2005

    • Author(s)
      Kohsuke Tsuchiya
    • Journal Title

      Infection and Immunity 73(in press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 細胞内寄生性細菌毒素蛋白による宿主サイトカイン誘導機構2004

    • Author(s)
      光山正雄
    • Journal Title

      炎症と免疫 12(4)

      Pages: 471-477

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] サイトカインの病態への関与:細菌感染症2004

    • Author(s)
      光山正雄
    • Journal Title

      医学のあゆみ 8

      Pages: 1793-1796

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Mechanism of host cytokine induction by protein toxin from intracellular bacteria (a review in Japanese)2004

    • Author(s)
      Mitsuyama, M.
    • Journal Title

      Ensho-to-Men'eki (Inflammatin and Immunity) 12

      Pages: 471-477

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Bacterial infection, the contribution of cytokines in the pathophysiology (a review in Japanese)2004

    • Author(s)
      Mitsuyama M.
    • Journal Title

      Igaku-no-Ayumi (Progress in Medicine) 209(8)

      Pages: 1793-1796

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Expression of IL-6 and TNFα in human alveolar epithelial cells is induced by invading, but not by adhering, Legionella pneumophila.2004

    • Author(s)
      Bing Chang
    • Journal Title

      Microbial Pathogenesis 37(6)

      Pages: 295-302

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 結核の免疫学2004

    • Author(s)
      光山 正雄
    • Journal Title

      医薬ジャーナル 40(2)

      Pages: 73-78

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 細胞内寄生性細菌毒素蛋白による宿主サイトカイン誘導機構2004

    • Author(s)
      光山 正雄
    • Journal Title

      炎症と免疫 12(4)

      Pages: 91-98

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 結核基礎研究の最前線2004

    • Author(s)
      光山 正雄
    • Journal Title

      Kekkaku(結核) 79(8)

      Pages: 487-501

    • NAID

      10013603670

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Seeligeriolysin O, a cholesterol-dependent cytolysin of Listeria seeligeri, induces gamma interferon from spleen cells of mice.2003

    • Author(s)
      Ito, Y.
    • Journal Title

      Infect.Immun. 71

      Pages: 234-241

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Impaired neutrophil maturation in truncated murine G-CSF receptor-transgenic mice.2003

    • Author(s)
      Mitsui, T.
    • Journal Title

      Blood 101

      Pages: 2990-2995

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Differences in gamma interferon production induced by listeriolysin O and ivanolysin O result in different levels of protective immunity in mice infected with Listeria monocytogenes and Listeria ivanovii.2003

    • Author(s)
      Kimoto, R.
    • Journal Title

      Infect.Immun. 71

      Pages: 2447-2454

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] 細菌感染と生体防御2003

    • Author(s)
      光山正雄
    • Journal Title

      内科 91(1)

      Pages: 152-155

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] 細胞内寄生菌感染とIL-182003

    • Author(s)
      光山正雄
    • Journal Title

      臨床免疫 39(1)

      Pages: 41-47

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] 細胞内寄生菌感染とNO2003

    • Author(s)
      土屋晃介
    • Journal Title

      医学のあゆみ 204(9)

      Pages: 679-683

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Differences in gamma interferon production induced by listeriolysin O and ivanolysin O result in different levels of protective immunity in mice infected with Listeria monocytogenes and Listeria ivanovii.2003

    • Author(s)
      Kimoto, T.
    • Journal Title

      Infect.Immun. 71

      Pages: 2447-2454

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Bacterial infection and host defense (a review in Japanese)2003

    • Author(s)
      Mitsuyama, M.
    • Journal Title

      Naika (Internal Medicine) 91

      Pages: 152-155

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Intracellular parasitic infection and IL-18 (a review in Japanese)2003

    • Author(s)
      Mitsuyama, M.
    • Journal Title

      Rinshou-Men'eki (Clinical Immunology) 39

      Pages: 41-47

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Infection with intracellular bacteria and NO (a review in Japanese)2003

    • Author(s)
      Tsuchiya, K.
    • Journal Title

      Igaku-no-Ayumi (Progress in Medicine) 204

      Pages: 679-683

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Induction of gamma interferon and nitric oxide by truncated pneumolysin that lacks pore-forming activity.2002

    • Author(s)
      Baba, H.
    • Journal Title

      Infect.Immun. 70

      Pages: 107-113

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Essential role of interleukin 12 (IL-12) and Il-18 for gamma interferon production induced by listeriolysin O in the spleen cells of mice.2002

    • Author(s)
      Nomura, T.
    • Journal Title

      Infect.Immun. 70

      Pages: 1049-1055

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Dissociated linkage of cytokine-inducing activity and cytotoxicity to different domains of listeriolysin O from Listeria monocytogenes.2002

    • Author(s)
      Kohda, C.
    • Journal Title

      Infect.Immun. 70

      Pages: 1334-1341

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] リステリアの宿主認識・細胞内動態と宿主サイトカイン応答2002

    • Author(s)
      光山正雄
    • Journal Title

      細胞工学 21(2)

      Pages: 170-176

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] リステリア感染の分子構造と宿主の応答2002

    • Author(s)
      光山正雄
    • Journal Title

      Molecular Medicine 39(2)

      Pages: 164-171

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] リステリア菌の感染メカニズム2002

    • Author(s)
      光山正雄
    • Journal Title

      感染・炎症・免疫 32(3)

      Pages: 158-167

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Induction of gamma interferon and nitric oxide by truncated pneumolysin that lacks pore-forming activity.2002

    • Author(s)
      Baba H.
    • Journal Title

      Infect.Immun. 70

      Pages: 107-113

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Intracellular dynamics and host cytokine response to Listeria monocytogenes. (a review in Japanese)2002

    • Author(s)
      Mitsuyama, M.
    • Journal Title

      Saibou-Kougaku (Cell Technology) 21

      Pages: 170-176

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Molecular mechanism and host response in Listeria infection. (a review in Japanese)2002

    • Author(s)
      Mitsuyama, M.
    • Journal Title

      Molecular Medicine 39

      Pages: 164-171

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Mechanism of infection by Listeria monocytogenes (a review in Japanese)2002

    • Author(s)
      Mitsuyama, M.
    • Journal Title

      Infection, Inflammation and Immunity 32

      Pages: 158-167

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] 免疫学的プロトコール(分担執筆)2004

    • Author(s)
      野村卓正
    • Total Pages
      243
    • Publisher
      羊土社
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] 別冊医学のあゆみ サイトカイン-State of Arts(分担執筆)2004

    • Author(s)
      光山正雄
    • Total Pages
      406
    • Publisher
      医歯薬出版株式会社
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] 別冊医学のあゆみ サイトカイン(分担執筆)2004

    • Author(s)
      光山 正雄
    • Total Pages
      406
    • Publisher
      医歯薬出版
    • Related Report
      2004 Annual Research Report
  • [Book] Annual Review呼吸器2003(分担執筆)2003

    • Author(s)
      河村伊久雄
    • Total Pages
      282
    • Publisher
      中外医学社
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] 毒素タンパク質(廣川タンパク質化学第1巻)(分担執筆)2003

    • Author(s)
      光山正雄
    • Total Pages
      201
    • Publisher
      廣川書店
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] Annual Review免疫2004(分担執筆)2003

    • Author(s)
      光山正雄
    • Total Pages
      315
    • Publisher
      中外医学社
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] 標準微生物学 改訂第8版(分担執筆)2002

    • Author(s)
      光山正雄
    • Total Pages
      559
    • Publisher
      医学書院
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] 細菌学 第1版(分担執筆)2002

    • Author(s)
      光山正雄
    • Total Pages
      706
    • Publisher
      朝倉書店
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] 感染症の宿主防御機構-理論と実際-(分担執筆)2002

    • Author(s)
      光山正雄
    • Total Pages
      279
    • Publisher
      医薬ジャーナル社
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] 別冊・医学のあゆみ 免疫疾患その2(分担執筆)2002

    • Author(s)
      光山正雄
    • Total Pages
      570
    • Publisher
      医歯薬出版
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] 戸田新細菌学改訂32版(分担執筆)2002

    • Author(s)
      光山正雄
    • Total Pages
      1042
    • Publisher
      南山堂
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] 標準免疫学第2版(分担執筆)2002

    • Author(s)
      光山正雄
    • Total Pages
      522
    • Publisher
      医学書院
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Ito, Y., et al.: "Seeligeriolysin O, a cholesterol-dependent cytolysin of Listeria seeligeri, induces gamma interferon from spleen cells of mice"Infect.Immun.. 71(1). 234-241 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kimoto, T., et al.: "Differences in gamma interferon production induced by listeriolysin O and ivanolysin O result in different levels of protective immunity in mice infected with Listeria monocytogenes and Listeria ivanovii"Infect.Immun.. 71(5). 2447-2454 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Mitsui, T., et al.: "Impaired neutrophil maturation in truncated murine G-CSF receptor-transgenic mice"Blood. 101(8). 2990-2995 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 光山 正雄, 野村卓正: "細胞内寄生菌感染とIL-18"臨床免疫. 39(1). 41-47 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 光山正雄, 土屋晃介: "細胞内寄生菌感染とNO"医学のあゆみ. 204(9). 679-683 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 光山正雄: "結核免疫学の動向と課題"Kekkaku(結核). 78(1). 51-55 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 光山正雄: "Annual Review免疫(分担執筆)"中外医学社(東京). 315 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nomura, T et al.: "Essential role of interleukin 12 (IL-12) Il-18 for gamma interferon production induced by listeriolysin O in thespleen cells of mice"Infect.Immun.. 70(3). 1049-1055 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kohda, C.et al.: "Dissociated linkage of cytokine-inducing activity and cytotoxicity to different domains of listeriolysin O fromListeria monocytogenes"Infect.Immun.. 70(3). 1334-1341 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ito, Y.et al.: "Seeligeriolysin O, a cholesterol-dependent cytolysin of Listeria seeligeri, induces gamma interferon from spleen cells of mice"Infect.Immun.. 71(1). 234-241 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Mitsui, T.et al.: "Impaired neutrophil maturation in truncated murine G-CSF receptor-transgenic mice"Blood. 101(5)(in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kimoto, T.et al.: "Differences in gamma interferon production induced by listeriolysin O and ivanolysin O result in different levels of protectiveimmunity in mice infected with Listeria monocytogenes and Listeria ivanovii"Infect.Immun.. 71(5)(in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] 光山正雄: "リステリア菌の感染メカニズム"感染・炎症・免疫. 32(3). 158-167 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 光山正雄: "戸田新細菌学改訂第32版(分担執筆)"南山堂(東京). 1042 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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