Perturbation of macrophage function by virulence-associating determinants derived from Mycobacterium tuberculosis

• Project/Area Number: 19590443
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Bacteriology (including Mycology)
• Research Institution: Kyoto University
• Principal Investigator: KAWAMURA Ikuo Kyoto University, 医学研究科, 准教授 (20214695)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2008: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2007: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: 結核菌 / BCG / RD1 / マクロファージ / ネクローシス / カスパーゼ / PD-1 / サイトカイン / IL-18 / caspase-1 / CD4+T細胞 / 感染防御 / ミトコンドリア / ATP / PPE37

Research Abstract

結核菌ゲノム上に存在するRD1領域は、マクロファージのミトコンドリア内膜の傷害や、細胞質内カリウムの流出に関与する. その結果、結核菌感染マクロファージでは細胞死やカスパーゼ1の活性化が誘導される. 一方、PPE37は炎症性サイトカイン産生を抑制することで結核菌の病原性に寄与する. また、BCGを用いた感染実験で、宿主体内から菌が容易に排除されないのは、PD-1を介した抑制性シグナル経路が活性化されるためであることが示された.

Research Products

• [Journal Article] Dependency of caspase-1 activation induced in macrophages by Listeria monocytogenes on cytolysin listeriolysin O, after evasion from phagosome into the cytoplasm (2008)
  • Author(s): Hara, H., Tsuchiya, K., Nomura, T., Kawamura, I., Shoma, S., and Masao Mitsuyama, M
  • Journal Title: J. Immunol 180 Pages: 7859-7868
  • Peer Reviewed
• [Journal Article] Critical involvement of pneumolysin in production of IL-1a and caspase-1-dependentcytokines in infection with Streptococcus pneumoniae in vitro : a novel function of pneumolysin in caspase-1 activation (2008)
  • Author(s): Shoma, S., Tsuchiya, K., Kawamura, I., Nomura, T., Hara, H., Uchiyama, R., Daim, S., and Mitsuyama, M
  • Journal Title: Infect. Immun 76(4) Pages: 1547-1557
  • Peer Reviewed
• [Journal Article] 結核菌の病原性機序-細胞内寄生戦略 (2008)
  • Author(s): 河村伊久雄
  • Journal Title: Kekkaku 83 Pages: 690-693
  • NAID: 10025689144
• [Journal Article] 結核菌のマクロファー内生存機構 (2008)
  • Author(s): 河村伊久雄
  • Journal Title: Jpn. J. Leprosy 77 Pages: 219-224
• [Journal Article] Dependency of caspase-1 activation induced in macrophages by Listeria monocytogenes on cytolysin, listeriolysin 0, after evasion from phagosome into the cytoplasm (2008)
  • Author(s): Hara, H., Tsuchiya, K., Nomura, T., Kawamura, I., Shoma, S., Mitsuyama, M.
  • Journal Title: Journal of Immunology 180 Pages: 7859-7868
  • Peer Reviewed
• [Journal Article] Critical involvement of pneumolysin in production of interleukin-la and caspase-1-dependent cytokines in infection with Streptococcus pneumoniae in vitro : a novel function of pneumolysin in caspase-1 activation. (2008)
  • Author(s): Shoma, S., Tsuchiya, K., Kawamura, I., Nomura, T., Hara, H., Uchiyama, R., Daim, S., Mitsuyama, M.
  • Journal Title: Infection and Immunity 76 Pages: 1547-1557
  • Peer Reviewed
• [Journal Article] 結核菌のマクロファー内生存機構 (2008)
  • Author(s): 河村伊久雄
  • Journal Title: Japanease Journal of Leprosy 77 Pages: 219-224
• [Journal Article] RD1 region in mycobacterial genome is involved in the induction of neciorss in infected RAW264 cells via mitochondrial membrane damage and ATP depletion. (2007)
  • Author(s): Kaku, T., Kawamura, I., Uchiyama, R., Kurenuma, T., and Mitsuyama, M
  • Journal Title: FEMS Microbiol. Lett 274(2) Pages: 189-195
  • Peer Reviewed
• [Journal Article] Irreversible loss of membrane-binding activity of Listeria-derived cytolysins in non-acidic conditions : a distinct difference from allied cytolysins produced by other Gram-positive bacteria (2007)
  • Author(s): Nomura, T., Kawamura, I., Kohda, C., Baba, H., Ito, Y., Kimoto, T., Watanabe, I., and Mitsuyama, M
  • Journal Title: Microbiology 153 Pages: 2250-2258
  • Peer Reviewed
• [Journal Article] Cytolysin-dependent escape of the bacterium from the phagosome is required but not sufficient for induction of the Th1 immune response against Listeria monocytogenes infection : distinct role of Listeriolysin O determined by cytolysin gene replacement (2007)
  • Author(s): Hara, H., Ikuo Kawamura, Nomura, T., Tominaga, T., Tsuchiya, K., and Mitsuyama, M
  • Journal Title: Infect. Immun 75(8) Pages: 3791-3801
  • Peer Reviewed
• [Journal Article] Involvement of caspase-9 in the inhibition of necrosis of RAW 264 cells infected with Mycobacterium tuberculosis (2007)
  • Author(s): Uchiyama, R., Kawamura, I., Fujimura, T., Kawanishi, M., Tsuchiya, K., Tominaga, T., Kaku, T., Fukasawa, Y., Sakai, S., Nomura, T., and Mitsuyama, M
  • Journal Title: Infect. Immun 75(6) Pages: 2894-2902
  • Peer Reviewed
• [Journal Article] Critical involvement of pneumolysin in production of IL-la and caspase-1-dependent cytokines in infection with Streptococcus pneumoniae in vitro: a novel function of pneumolysin in caspase-1 activation. (2007)
  • Author(s): Shoma, S., Tsuchiya, K., Kawamura, I., et. al.
  • Journal Title: Infect. Immun. 76 Pages: 1547-1557
  • Peer Reviewed
• [Journal Article] RDI region on mycobacterial genome is involved in the induction of necrosis in infected RAW264 cells via mitchondrial membrane damage and ATP depletion. (2007)
  • Author(s): Kaku T., Kawamura, I., Uchiyama, R., et. al.
  • Journal Title: FEMS Microbiol. Lett. 274 Pages: 189-195
  • Peer Reviewed
• [Journal Article] Irreversible loss of membrane-binding activity of Listeria-derived cytolysins in non-acidic conditions: a distinct difference from allied cytolysins produced by other Gram-positive bacteria. (2007)
  • Author(s): Nomura, T., Kawamura, I., Kohda, C., et. al.
  • Journal Title: Microbiology 153 Pages: 2250-2258
  • Peer Reviewed
• [Journal Article] Cytolysin-dependent escape of the bacterium from the phagosome is required but not sufficient for induction of the Thl immune response against Listeria monocytogenes infection: distinct role of listeriolysin O determined by cytolysin gene replacement. (2007)
  • Author(s): Hara, H., Kawamura, I., Nomura, T., et. al.
  • Journal Title: Infect. Immun. 75 Pages: 3791-3801
  • Peer Reviewed
• [Journal Article] Involvement of caspase-9 in the inhibition of necrosis of RAW264 cells infected with Mycobacterium tuberculosis. (2007)
  • Author(s): Uchiyama, R., Kawamura, I., Fujimura, T., et. al.
  • Journal Title: Infect. Immun. 75 Pages: 2894-2902
  • Peer Reviewed
• [Presentation] The PD-1 : PD-L1 pathway is involved in the persistent infection with Mycobacterium bovis BCG (2009)
  • Author(s): 酒井俊祐、河村伊久雄、内山良介、光山正雄
  • Organizer: 第82回日本細菌学会総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2009-03-13
• [Presentation] Mycobacterium tuberculosis PPE37 protein alters the early cytokine response of macrophages (2009)
  • Author(s): Sylvia Daim、河村伊久雄、原英樹、申艶娜、暮沼武士、光山正雄
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2009-03-13
• [Presentation] The PD-1 : PD-L1 pathway is involved in the persistent infection of Mycobacterium bovis BCG. (2009)
  • Author(s): 酒井俊祐, 河村伊久雄, 内山良介, 光山正雄
  • Organizer: 第82回日本細菌学会総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2009-03-13
• [Presentation] Mycobacterium tuberculosis PPE37 protein alters the early cytokine response of macrophages. (2009)
  • Author(s): 酒井俊祐, Daim, S., 河村伊久雄, 原英樹, 申艶那, 暮沼武士, 光山正雄
  • Organizer: 第82回日本細菌学会総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2009-03-13
• [Presentation] Possible role of PPE37 protein in Mycobacterium tuberculosis pathogenesis (2008)
  • Author(s): Daim, S., Kawamura, I., Kurenuma, T., and Mitsuyama, M
  • Organizer: 第38回日本免疫学会総会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2008-12-02
• [Presentation] The PD-1 : PD-L1 pathway inhibits the protective immunity and cotributes to the bacterial persistence in mycobacterial infection (2008)
  • Author(s): Sakai, S., Kawamura, I., Uchiyama, R., Okazaki, T., and Mitsuyama, M
  • Organizer: 第38回日本免疫学会総会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2008-12-02
• [Presentation] Possible role of PPE37 protein in Mycobacterium tuberculosis (2008)
  • Author(s): Daim, S., 河村伊久雄, 暮沼武士, 光山正雄
  • Organizer: 第38回日本免疫学会総会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2008-12-02
• [Presentation] The PD-1 : PD-L1 pathway inhibits the protective immunity and contributes to the bacterial persistence in mycobacterial infection. (2008)
  • Author(s): 酒井俊祐, 河村伊久雄, 内山良介, 岡崎拓, 光山正雄
  • Organizer: 第38回日本免疫学会総会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2008-12-02
• [Presentation] BCG持続感染の成立におけるPD-1/PD-L1を介した抑制生シグナル伝達経路の関与 (2008)
  • Author(s): 酒井俊祐、河村伊久雄、内山良介、光山正雄
  • Organizer: 第61回日本細菌学会関西支部総会
  • Place of Presentation: 京都大学芝欄会館
  • Year and Date: 2008-11-08
• [Presentation] BCG持続感染におけるPD-1/PD-L1を介した抑制性シグナル伝達経路の解析 (2008)
  • Author(s): 酒井俊祐, 河村伊久雄, 内山良介, 光山正雄
  • Organizer: 第61回日本細菌学会関西支部総会
  • Place of Presentation: 京都大学芝蘭会館
  • Year and Date: 2008-11-08
• [Presentation] 結核菌およびBCGの持続感染における免疫抑制受容体PD-1の役割 (2008)
  • Author(s): 酒井俊祐、河村伊久雄、内山良介、光山正雄
  • Organizer: 第19回日本生体防御学会
  • Place of Presentation: 北海道大学学術交流会館
  • Year and Date: 2008-07-12
• [Presentation] 結核菌およびBCGの持続感染における免疫抑制受容体PD-1の役割 (2008)
  • Author(s): 酒井俊祐, 河村伊久雄, 内山良介, 光山正雄
  • Organizer: 第19回日本生体防御学会
  • Place of Presentation: 北海道大学交流会館
  • Year and Date: 2008-07-11
• [Presentation] RD1 region in mycobacterial genome is involved in the induction of necrosis in infected macrophages via mitochondrial membrane damage and ATP depletion (2008)
  • Author(s): Kawamura, I., Kaku, T., Uchiyama, R., Kurenuma, T., and Mitsuyama, M
  • Organizer: US-Japan Cooperative Medical Science Program The 43^rd Tuberculosis and Leprosy Research Conference
  • Place of Presentation: 米国メリーランド州ボルチモア市
  • Year and Date: 2008-07-08
• [Presentation] RD1 region in mycobacterial genome is involved in the induction of necrosis in infected macrophages via mitochondrial membrane damage and ATP depletion. (2008)
  • Author(s): Kawamura, I., Kaku, T., Uchiyama, R., Kurenuma, T., Mitsuyama, M.
  • Organizer: The 43rd Tuberculosis and Leprosy Research Conference
  • Place of Presentation: 米国ボルチモア市
  • Year and Date: 2008-07-08
• [Presentation] 結核菌病原遺伝子領域RD1が関与するIFN-g産生誘導機序の解析 (2008)
  • Author(s): 暮沼武士、内山良介、河村伊久雄、光山正雄
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2008-03-26
• [Presentation] Possible role of PPE37 protein in Mycobacterium tuberculosis pathogenesis (2008)
  • Author(s): Daim, S., Kawamura, I., Mitsuyama, M
  • Organizer: 第82回日本細菌学会総会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2008-03-25
• [Presentation] PD-1-PD-L1 pathway inhibits Th1immune response during mycobacterial infection (2008)
  • Author(s): 酒井俊祐、河村伊久雄、内山良介、光山正雄
  • Organizer: 第82回日本細菌学会総会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2008-03-25
• [Presentation] Mycobacterium mammalian cell entry protein IA (McelA)-mediated adherence enhances the chemokine production by A549 alveolar epithelial cells (2007)
  • Author(s): Mitsuyama, M. & Kawamura, I.
  • Organizer: The 42th US-Japan tuberculosis and leprosy research conference
  • Place of Presentation: Zhengzhou, China
  • Year and Date: 2007-12-14
• [Presentation] PD-1/PD-L1 pathway down-regulates Th1 immune response during mycobacterial infection (2007)
  • Author(s): Sakai, S., Kawamura, I., Uchiyama, R., and Mitsuyama, M
  • Place of Presentation: グランドプリンスホテル新高輪(東京)
  • Year and Date: 2007-11-22
• [Presentation] Involvement of caspase-9 in the inhibition of necrosis of peritoneal macrophages infected with Mycobacterium tuberculosis (2007)
  • Author(s): Uchiyama, R., Kawamura, I., Tsuchiya, K., Tominaga, T., Sakai, S., Nomura, T., and Mitsuyama, M
  • Place of Presentation: グランドプリンスホテル新高輪(東京)
  • Year and Date: 2007-11-21
• [Presentation] 結核菌のRD1領域はミトコンドリア傷害とATP枯渇により感染マクロファージのネクローシス誘導に関与する (2007)
  • Author(s): Kurenuma, T., Uchiyama, R., Kawamura, I., and Mitsuyama, M
  • Place of Presentation: グランドプリンスホテル新高輪(東京)
  • Year and Date: 2007-11-21
• [Presentation] 結核菌感染マクロファージのネクローシス誘導における病原遺伝子領域RD1 の関与とその誘導機序について (2007)
  • Author(s): 暮沼武士、角泰人、内山良介、河村伊久雄、光山正雄
  • Place of Presentation: 大阪大学銀杏会館
  • Year and Date: 2007-11-10
• [Presentation] Mycobacterial mammalian cell entry protein 1A (Mce 1A)-mediated adherence enhances the chemokine production by A549 alveolar epithelial cells (2007)
  • Author(s): Mitsuyama, M., and Kawamura, I
  • Place of Presentation: 米国メリーランド州ボルチモア市
  • Year and Date: 2007-09-14
• [Presentation] 結核菌感染マクロファージのネクローシス誘導における病原遺伝子領域RD1の関与とその誘導機序 (2007)
  • Author(s): 暮沼武士、内山良介、河村伊久雄、光山正雄
  • Place of Presentation: 九州大学西新プラザ
  • Year and Date: 2007-07-26
• [Presentation] 結核菌細胞内侵入因子Mce1Aを介したA549肺胞上皮細胞からのケモカイン産生誘導 (2007)
  • Author(s): 内山良介、河村伊久雄、光山正雄
  • Place of Presentation: 九州大学西新プラザ
  • Year and Date: 2007-07-26
• [Presentation] Involvement of caspase-9 in the inhibition of necrosis of peritoneal macrophages infected with M. tuberculosis. (2007)
  • Author(s): Uchiyama, R., Kawamura, I., Tsuchiya, K., et. al.
  • Organizer: 第37回日本免疫学会総会
  • Place of Presentation: 品川プリンスホテル、東京
• [Presentation] 結核菌のRD1領域はミトコンドリア傷害とATP枯渇により感染マクロファージのネクローシス誘導に関与する (2007)
  • Author(s): Kurenuma, T., Uchiyama, R., Kawamura, I., et. al.
  • Organizer: 第37回日本免疫学会総会
  • Place of Presentation: 品川プリンスホテル、東京
• [Book] 蛋白質核酸酵素増刊「感染現象」細胞内寄生菌のマクロファージ内生存戦略 (2009)
  • Author(s): 土屋晃介、河村伊久雄、光山正雄(分担)
  • Publisher: 共立出版
• [Remarks]
  • URL: http://bisei15.mb.med.kyoto-u.ac.jp
• [Remarks]
  • URL: http://bisei15.mb.med.kyoto-u.ac.jp/
• [Remarks]
  • URL: http://bisei15.mb.med.kyoto-u.ac.jp