Elucidation of function of increasing toxin in the streptococcal toxic shock syndrome clinical isolates and of the regulation

• Project/Area Number: 20790345
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Bacteriology (including Mycology)
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: IKEBE Tadayoshi 国立感染症研究所, 細菌第一部, 主任研究官 (20333362)
• Project Period (FY): 2008 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2011: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2010: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2009: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2008: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: 病原性 / 劇症型溶連菌感染症 / Streptococcus pyogenes

Research Abstract

Streptococcal toxic shock syndrome(STSS) is a severe invasive infection characterized by the sudden onset of shock and multiorgan failure ; it has a high mortality rate. In the present study, mutations of another negative regulator, rgg, were also found in clinical isolates of STSS patients. The rgg mutants from STSS clinical isolates enhanced lethality and impaired various organs in the mouse models and precluded their being killed by human neutrophils. When we assessed the mutation frequency of rgg gene among S. pyogenes isolates from STSS and non-invasive infections, about 25% of the STSS isolates had mutations of rgg gene, while isolates from patients with non-invasive disease had significantly fewer mutations in this gene(1.7%). The results of the present study suggest that mutations in the negative regulators csrS/csrR and rgg of S. pyogenes are crucial factors in the pathogenesis of STSS, as they lead to the overproduction of multiple virulence factors.

Research Products

• [Journal Article] Interferon-γ-producing immature myeloid cells confer protection against severe invasive group A Streptococcus infections (2012)
  • Author(s): Matsumura T, Ato M, Ikebe T, Ohnishi M, Watanabe H, Kazuo Kobayashi
  • Journal Title: Nat Commun Volume: 3 Issue: 1 Pages: 678-678
  • DOI: 10.1038/ncomms1677
  • Peer Reviewed
• [Journal Article] Highly frequent mutations in negative regulators of multiple virulence genes in group A streptococcal toxic shock syndrome isolates (2010)
  • Author(s): Ikebe T, Ato M, Matsumura T, Hasegawa H, Sata T, Kobayashi K, Watanabe H
  • Journal Title: PLoS Pathog Volume: 6 Issue: 4 Pages: e1000832-e1000832
  • DOI: 10.1371/journal.ppat.1000832
  • Peer Reviewed
• [Journal Article] The Working Group forβ-hemolytic Streptococci in Japan. Emergence of clindamycin-resistant Streptococcus pyogenes isolates obtained from patients with severe invasive infections in Japan (2010)
  • Author(s): Ikebe T, Wada A, Oguro Y, Ogata K, Katsukawa C, Isobe J, Shima T, Suzuki R, Ohya H, Tominaga K, Okuno R, Uchitani Y, Watanabe H
  • Journal Title: Jpn J Infect Dis Volume: 63 Pages: 304-305
  • Peer Reviewed
• [Journal Article] The Working Group forβ-hemolytic Streptococci in Japan. Surveillance of severe invasive group G streptococcal infections during 2002-2008 in Japan (2010)
  • Author(s): Ikebe T, Oguro Y, Ogata K, Katsukawa C, Isobe J, Shima T, Suzuki R, Ohya H, Tominaga K, Okuno R, Uchitani Y, Tada Y, Okabe N, Watanabe H
  • Journal Title: Jpn J Infect Dis Volume: 63 Pages: 372-375
  • Peer Reviewed
• [Journal Article] Invasive group A streptococcal infection in pregnancy (2010)
  • Author(s): Yamada T, Yamada T, Yamamura MK, Katabami K, Hayakawa M, Tomaru U, Shimada S, Morikawa M, Seki T, Ariga S, Ishikawa K, Ikebe T, Gando S, Minakami H
  • Journal Title: J Infect Volume: 60 Pages: 417-424
  • Peer Reviewed
• [Journal Article] Highly frequent mutations in negative regulators of multiple virulence genes in group A streptococcal toxic shock syndrome isolates. (2010)
  • Author(s): Ikebe T, Ato M, Matsumura T, Hasegawa H, Sata T, Kobayashi K, Watanabe H.
  • Journal Title: PLoS Pathog 6
  • Peer Reviewed
• [Journal Article] The Working Group for β-hemolytic Streptococci in Japan. Surveillance of severe invasive group G streptococcal infections during 2002-2008 in Japan. (2010)
  • Author(s): Ikebe T, Oguro Y, Ogata K, Katsukawa C, Isobe J, Shima T, Suzuki R, Ohya H, Tominaga K, Okuno R, Uchitani Y, Tada Y, Okabe N, Watanabe H
  • Journal Title: Jpn J Infect Dis. 63 Pages: 372-375
  • Peer Reviewed
• [Journal Article] Highly frequent mutations in negative regulators of multiple virulence genes in group A streptococcal toxic shock syndrome isolates. (2010)
  • Author(s): Ikebe T, Ato M, Matsumura T, Hasegawa H, Sata T, Kobayashi K, Watanabe H.
  • Journal Title: PLoS Pathogens Volume: 6
  • Peer Reviewed
• [Journal Article] Emergence of clindamycin-resistant Streptococcus pyogenes isolates obtained from patients with severe invasive infections in Japan. (2010)
  • Author(s): Ikebe T, Wada A, Oguro Y, Ogata K, Katsukawa C, Isobe J, Shima T, Suzuki R, Ohya H, Tominaga K, Okuno R, Uchitani Y, Watanabe H, The Working Group for β-hemolytic Streptococci in Japan.
  • Journal Title: Jpn J Infect Dis Volume: 63 Pages: 304-305
  • Peer Reviewed
• [Journal Article] Surveillance of severe invasive group G streptococcal infections during 2002-2008 in Japan. (2010)
  • Author(s): Ikebe T, Oguro Y, Ogata K, Katsukawa C, Isobe J, Shima T, Suzuki R, Ohya H, Tominaga K, Okuno R, Uchitani Y, Tada Y, Okabe N, Watanabe H, The Working Group for β-hemolytic Streptococci in Japan.
  • Journal Title: Jpn J Infect Dis Volume: 63 Pages: 372-375
  • Peer Reviewed
• [Journal Article] Invasive group A streptococcal infection in pregnancy. (2010)
  • Author(s): Yamada T, Yamada T, Yamamura MK, Katabami K, Hayakawa M, Tomaru U, Shimada S, Morikawa M, Seki T, Ariga S, Ishikawa K, Ikebe T, Gando S, Minakami H.
  • Journal Title: J Infect. Volume: 60 Pages: 417-424
  • Peer Reviewed
• [Journal Article] Highly frequent mutations in negative regulators of multiple virulence genes in group A streptococcal toxic shock syndrome isolates. (2010)
  • Author(s): Ikebe T, Ato M, Matsumura T, Hasegawa H, Sata T, Kobayashi K, Watanabe H.
  • Journal Title: PLoS Pathogens (In press)
  • Peer Reviewed
• [Journal Article] 劇症型溶血性レンサ球菌感染症. (2010)
  • Author(s): 池辺忠義
  • Journal Title: 公衆衛生 74巻 Pages: 34-38
• [Journal Article] 劇症型溶血性レンサ球菌感染症の発症機序-菌の免疫回避機構と菌の特性- (2009)
  • Author(s): 池辺忠義、阿戸学、小林和夫、渡辺治雄
  • Journal Title: 感染症学雑誌 Volume: 83 Pages: 485-489
  • NAID: 10025556568
• [Journal Article] Working Group for Beta-Haemolytic Streptococci in Japan. T serotyping of Streptococcus pyogenes in Aichi Prefecture, Japan isolated between 2003 and 2007 (2009)
  • Author(s): Matsumoto M, Yamaguchi I, Sasano M, Hori M, Ikezaki K, Shimizu S, Nishiyama Y, Sato N, Tsuchiya H, Suzuki M, Minagawa H
  • Journal Title: Jpn J Infect Dis Volume: 62 Pages: 168-169
  • Peer Reviewed
• [Journal Article] 劇症型溶血性レンサ球菌感染症の発症機序-菌の免疫回避機構と菌の特性- (2009)
  • Author(s): 池辺忠義、阿戸学、小林和夫、渡辺治雄
  • Journal Title: 感染症学雑誌 83 Pages: 485-489
  • NAID: 10025556568
  • Peer Reviewed
• [Journal Article] 劇症型溶血性レンサ球菌感染症の発症機序-菌の免疫回避機構と菌の特性- (2009)
  • Author(s): 池辺忠義、阿戸学、小林和夫、渡辺治雄
  • Journal Title: 感染症学雑誌 83巻 Pages: 485-489
  • NAID: 10025556568
  • Peer Reviewed
• [Journal Article] T serotyping of Streptococcus pyogenes in Aichi Prefecture, Japan isolated between 2003 and 2007. (2009)
  • Author(s): Matsumoto M, Yamaguchi I, Sasano M, Hori M, Ikezaki K, Shimizu S, Nishiyama Y, Sato N, Tsuchiya H, Suzuki M, Minagawa H, Working Group for Beta-Haemolytic Streptococci in Japan.
  • Journal Title: Japanese Journal of Infectious Diseases Vol.62 Pages: 168-169
  • Peer Reviewed
• [Journal Article] 劇症型A群レンサ球菌感染症における好中球傷害の機序. (2009)
  • Author(s): 阿戸学、池辺忠義
  • Journal Title: 臨床免疫・アレルギー科 51巻 Pages: 406-413
  • NAID: 40016663764
• [Journal Article] Incompetence of neutrophils to invasive group A streptococcus is attributed to induction of plural virulence factors by dysfunction of a regulator (2008)
  • Author(s): Ato M, Ikebe T, Kawabata H, Takemori T, Watanabe H
  • Journal Title: PLoS ONE Volume: 3 Issue: 10 Pages: e3455-e3455
  • DOI: 10.1371/journal.pone.0003455
  • Peer Reviewed
• [Journal Article] Genetic features of clinical isolates of Streptococcus dysgalactiae subsp. equisimilis possessing Lancefield's group A antigen (2008)
  • Author(s): Tanaka, D., Isobe, J., Watahiki, M., Nagai, Y., Katsukawa, C., Kawahara, R., Endoh, M., Okuno, R., Kumagai, N., Matsumoto, M., Morikawa, Y., Ikebe, T., Watanabe, H., and the Working Group for Group A Streptococci in Japan
  • Journal Title: J. Clin. Microbiol Volume: 46 Pages: 1526-1529
  • Peer Reviewed
• [Journal Article] Incompetence of neutrophils to invasive group A streptococcus is attributed to induction of plural virulence factors by dysfunction of a regulator. (2008)
  • Author(s): Ato M, Ikebe T, Kawabata H, Takemori T, Watanabe H.
  • Journal Title: PLoS ONE 3
  • Peer Reviewed
• [Journal Article] Incompetence of neutrophils to invasive group A streptococcus is attributed to induction of plural virulence factors by dysfunction of a regulator. (2008)
  • Author(s): Ato M, et al.
  • Journal Title: PLoS ONE 3
  • Peer Reviewed
• [Journal Article] Genetic features of clinical isolates of Streptococcus dysgalactiae subs p. equisimilis possessing Lancefield's group A antigen. (2008)
  • Author(s): Tanaka D., et al.
  • Journal Title: J. Clin. Microbiol. 46 Pages: 1526-1529
  • Peer Reviewed
• [Journal Article] 劇症型溶血性レンサ球菌感染症の発症機序-菌の特徴と免疫回避機構- (2008)
  • Author(s): 池辺忠義ら
  • Journal Title: BIO Clinica 23 Pages: 1321-1326
• [Presentation] 溶血性レンサ球菌による劇症型感染症の細菌学的解析 (2012)
  • Author(s): 池辺忠義
  • Organizer: 平成23年度第21回学会賞受賞者特別講演会
  • Place of Presentation: 東京
  • Year and Date: 2012-01-27
• [Presentation] 溶血性レンサ球菌による劇症型感染症の細菌学的解析 (2012)
  • Author(s): 池辺忠義
  • Organizer: 平成23年度第21回学会賞受賞者特別講演会
  • Place of Presentation: 東京(招待講演)
  • Year and Date: 2012-01-27
• [Presentation] 劇症型A群レンサ球菌感染症臨床分離株における遺伝子発現制御因子の変異 (2011)
  • Author(s): 池辺忠義
  • Organizer: 第94回日本細菌学会関東支部総会-若手対象ワークショップ:細菌学の新たな潮流-
  • Place of Presentation: 東京
• [Presentation] 劇症型溶血性レンサ球菌感染症分離株でみられたクリンダマイシン耐性株の増加 (2011)
  • Author(s): 池辺忠義、小黒祐子、嶋智子、奥野ルミ、大屋日登美、勝川千尋、富永潔、緒方喜久代、大西真、渡邉治雄
  • Organizer: 第20回Lancefieldレンサ球菌研究会および第43回レンサ球菌感染症研究会合同学会
  • Place of Presentation: 愛知
• [Presentation] Molecular Epidemiology of group A Streptococcus isolated from patients with severe invasive infections in Japan during 2004-2010 (2011)
  • Author(s): Ikebe T, Katsukawa C, Ohya H, Suzuki R, Oguro Y, Tominaga K, Shima T, Isobe J, Ogata K, Okuno R, Fujimoto T, Tada Y, Okabe N, Ohnishi M, Watanabe H, The Working Group forβ-hemolytic Streptococci in Japan
  • Organizer: XVIII Lancefield International Symposium
  • Place of Presentation: Italy, Palermo
• [Presentation] The protective role of a novel population of interferon-γproducing cells in severe invasive Group A streptococcal infections (2011)
  • Author(s): Matsumura T, Ikebe T, Ohnishi M, Watanabe H, Kobayashi K, Ato M
  • Organizer: XVIII Lancefield International Symposium
  • Place of Presentation: Italy, Palermo
• [Presentation] Contact with group A Streptococcus isolated from severe invasive infections induces rapid necrosis of human neutrophils (2011)
  • Author(s): Ato M, Ikebe T, Matsumura T, Ohnishi M, Watanabe H, Kobayashi K
  • Organizer: International Union of Microbiological Societies 2011 Congress
  • Place of Presentation: Sapporo
• [Presentation] A novel interferon-γ-producing subpopulations of immature myeloid cells confers protection from severe invasive group A Streptococcus infections (2011)
  • Author(s): Matsumura T, Ikebe T, Ohnishi M, Watanabe H, Kobayashi K, Ato M
  • Organizer: The Joint International Meeting of The 76^<th> Annual Meeting of the Japanese Society for Interferon and Cytokine Research, and The 19^<th> International Symposium of Macrophage Molecular and Cell Biology 2011
  • Place of Presentation: Osaka
• [Presentation] 劇症型溶血性レンサ球菌感染症における環状核骨髄系細胞の保護的役割 (2011)
  • Author(s): 松村隆之、池辺忠義、大西真、渡邉治雄、小林和夫、阿戸学
  • Organizer: 第9回感染症沖縄フォーラム
  • Place of Presentation: 沖縄
• [Presentation] The protective role of a novel population of interferon-γ producing cells in severe invasive Group A streptococcal infections… (2011)
  • Author(s): Matsumura T, Ikebe T, Ohnishi M, Watanabe H, Kobayashi K, Ato M
  • Organizer: XVIII Lancefield International Symposium
  • Place of Presentation: Italy, Palermo
• [Presentation] 劇症型溶レン菌感染症臨床分離株で高頻度でみられる負の転写制御因子の変異 (2010)
  • Author(s): 池辺忠義、阿戸学、松村隆之、長谷川秀樹、小黒祐子、嶋智子、奥野ルミ、大屋日登美、勝川千尋、富永潔、緒方喜久代、佐多徹太郎、小林和夫、大西真、渡邉治雄
  • Organizer: 第19回Lancefieldレンサ球菌研究会および第42回レンサ球菌感染症研究会合同学会
  • Place of Presentation: 東京
• [Presentation] Streptococcus dysgalactiae subsp. dysgalactiaeによる初めてのヒト侵襲性感染症例 (2010)
  • Author(s): 外山雅美、長野則之、長野由紀子、池辺忠義、和田昭仁、荒川宜親
  • Organizer: 第19回Lancefieldレンサ球菌研究会および第42回レンサ球菌感染症研究会合同学会
  • Place of Presentation: 東京
• [Presentation] The defensive role of interferon-γproduced by myeloid cells in invasive group A Streptococcus infection (2010)
  • Author(s): Matsumura T, Ikebe T, Watanabe H, Kobayashi K, Ato M
  • Organizer: 18th International Symposium on Molecular Cell Biology of Macrophages
  • Place of Presentation: 熊本
• [Presentation] Identification of IFN-gamma producing cells in severe invasive group A streptococcal infection. (2010)
  • Author(s): Matsumura T, Ikebe T, Watanabe H, Kobayashi K, Ato M
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: 神戸
• [Presentation] 日本における劇症型溶血性レンサ球菌感染症臨床分離株のemm遺伝子型とcsrS遺伝子の変異頻度 (2010)
  • Author(s): 池辺忠義、緒方喜久代、奥野ルミ、嶋智子、大屋日登美、渡辺治雄
  • Organizer: 第83回日本細菌学会総会
  • Place of Presentation: 横浜
• [Presentation] 劇症型レンサ球菌感染症の重篤化に関わる病原因子の解明 (2010)
  • Author(s): 池辺忠義
  • Organizer: 第21回日本臨床微生物学会総会
  • Place of Presentation: 東京
• [Presentation] 劇症型溶血性レンサ球菌感染症におけるインターフェロンγ産生細胞の解析 (2010)
  • Author(s): 松村隆之,池辺忠義,渡邉治雄,小林和夫,阿戸学
  • Organizer: 第8回感染症沖縄フォーラム
  • Place of Presentation: 沖縄
• [Presentation] 劇症型溶血性レンサ球菌感染症における遺伝子発現調節因子の変異と好中球傷害 (2010)
  • Author(s): 阿戸学、松村隆之、池辺忠義、渡邉治雄、小林和夫
  • Organizer: 第8回感染症沖縄フォーラム
  • Place of Presentation: 沖縄
• [Presentation] The defensive role of interferon-γ produced by myeloid cells in invasive group A Streptococcus infection (2010)
  • Author(s): Matsumura T, Ikebe T, Watanabe H, Kobayashi K, Ato M.
  • Organizer: 18th International Symposium on Molecular Cell Biology of Macrophages
  • Place of Presentation: 熊本
• [Presentation] Identification of IFN-gamma producing cells in severe invasive group A streptococcal infection (2010)
  • Author(s): Matsumura T, Ikebe T, Watanabe H, Kobayashi K, Ato M.
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: 神戸
• [Presentation] Streptococcus dysgalactiae subsp.dysgalactiaeによる初めてのヒト侵襲性感染症例 (2010)
  • Author(s): 外山雅美、長野則之、長野由紀子、池辺忠義、和田昭仁、荒川宜親
  • Organizer: 第19回Lancefieldレンサ球菌研究会および第42回レンサ球菌感染症研究会合同学会
  • Place of Presentation: 東京
• [Presentation] 劇症型溶血性レンサ球菌感染症におけるインターフェロンγ産生細胞の解析. (2010)
  • Author(s): 松村隆之, 池辺忠義, 渡邉治雄, 小林和夫, 阿戸学
  • Organizer: 第8回感染症沖縄フォーラム
  • Place of Presentation: 沖縄
• [Presentation] 劇症型溶血性レンサ球菌感染症臨床分離株におけるcsrS変異の解析 (2009)
  • Author(s): 池辺忠義、阿戸学、川端寛樹、小林和夫、渡辺治雄
  • Organizer: 第82回日本細菌学会総会
  • Place of Presentation: 愛知
• [Presentation] 劇症型感染分離溶血性レンサ球菌株はストレプトリジンOおよび接触依存的にヒト好中球を傷害する (2009)
  • Author(s): 阿戸学、池辺忠義、渡辺治雄、小林和夫
  • Organizer: 第82回日本細菌学会総会
  • Place of Presentation: 愛知
• [Presentation] Streptococcus pyogenesにおけるバイオフィルム形成遺伝子の検討 (2009)
  • Author(s): 泉福英信、池辺忠義、河原井武人、渡辺治雄
  • Organizer: 第82回日本細菌学会総会
  • Place of Presentation: 愛知
• [Presentation] Streptococcus dysgalactiae subsp. dysgalactiaeによる初めてのヒト侵襲性感染症例 (2009)
  • Author(s): 長野則之、池辺忠義、和田昭仁、長野由紀子、諏訪直生、外山雅美、荒川宜親
  • Organizer: 第83回日本感染症学会総会
  • Place of Presentation: 東京
• [Presentation] 劇症型溶血性レンサ球菌感染症患者分離株によるヒト好中球ネクローシス誘導機構の解析 (2009)
  • Author(s): 松村隆之、池辺忠義、渡邉治雄、小林和夫、阿戸学
  • Organizer: 第7回感染症沖縄フォーラム
  • Place of Presentation: 沖縄
• [Presentation] Involvement of IFN-γand IL-6 in severe invasive group A streptococcus infection (2009)
  • Author(s): Matsumura, T., Ikebe, T., Watanabe, H., Kobayashi, K. Ato, M
  • Organizer: 17th International Symposium on Molecular Cell Biology of Macrophage
  • Place of Presentation: Ishikawa
• [Presentation] Streptococcus dysgalactiae subsp. dysgalactiaeによる初めてのヒト侵襲性感染症例. (2009)
  • Author(s): 長野則之、池辺忠義、和田昭仁、長野由紀子、諏訪直生、外山雅美、荒川宜親
  • Organizer: 第83回日本感染症学会総会
  • Place of Presentation: 東京
• [Presentation] Involvement of IFN-γa nd IL-6 in severe invasive group A streptococcus infection. (2009)
  • Author(s): Matsumura, T., Ikebe, T., Watanabe, H., Kobayashi, K.Ato, M.
  • Organizer: 17th International Symposium on Molecular Cell Biology of Macrophage
  • Place of Presentation: Ishikawa
• [Presentation] Impairment of global regulatory network of Streptococcus pyogenes virulence genes provokes neutrophil incompetence and subsequent streptococcal toxic shock-like syndrome (2008)
  • Author(s): Ikebe, T., Ato, M., Kobayashi, K., Watanabe, H
  • Organizer: Forum of the network of research centers on infectious diseases
  • Place of Presentation: Hanoi
  • Year and Date: 2008-10-06
• [Presentation] Impairment of global regulatory network of Streptococcus pyogenes virulence genes provokes neutrophil incompetence and subsequent streptococcal toxic shock-like syndrome. (2008)
  • Author(s): Ikebe, T.
  • Organizer: Forum of the network of research centers on infectious diseases
  • Place of Presentation: ベトナム、ハノイ
  • Year and Date: 2008-10-06
• [Presentation] 劇症型溶血性レンサ球菌感染症の発症機序 (2008)
  • Author(s): 池辺忠義
  • Organizer: 第82回日本感染症学会総会
  • Place of Presentation: 島根
• [Presentation] Impairment of global regulatory network of Streptococcus pyogenes virulence genes provokes neutrophil incompetence and subsequent streptococcal toxic shock-like syndrome. (2008)
  • Author(s): Ikebe, T., Ato, M., Kobayashi, K., Watanabe, H.
  • Organizer: Forum of the network of research centers on infectious diseases.
  • Place of Presentation: Hanoi.
• [Book] 豚レンサ球菌感染症.Inズーノシスハンドブック (2009)
  • Author(s): 池辺忠義、常彬
  • Total Pages: 232
  • Publisher: Medical Science