Virulence mechanisms in hypervirulent strains of group A streptococci

• Project/Area Number: 25460545
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Bacteriology (including mycology)
• Research Institution: Kitasato University
• Principal Investigator: Matsui Hidenori 北里大学, 感染制御科学府, 講師 (30219373)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 細菌 / 感染症 / CD46 / マウス感染モデル / レンサ球菌 / レンサ球菌毒素性ショック症候群 / 骨破壊 / RANKL / レンサ球菌毒素生ショック症候群

Outline of Final Research Achievements

Virulent and avirulent strains of group A streptococcus (GAS) emm type 1 were simultaneously isolated from a single patient suffering from streptococcal meningitis. The whole-genome sequencing and comparative genomic analysis revealed the possibility that a spontaneous point mutation in the rocA gene led to the hypervirulent phenotype of emm1 GAS associated with the suppression of covR expression. Meanwhile, the emm1 GAS strain GAS472 was isolated from a patient suffering from streptococcal toxic shock-like syndrome. CD46 transgenic (Tg) mice developed necrotizing fasciitis associated with osteoclast-mediated progressive and severe bone destruction in the hind paws after subcutaneous infection with GAS472. GAS472 infection induced expression of the receptor activator of nuclear factor-κB ligand (RANKL) in heterogeneous bone marrow cells. Therefore, GAS472 infection induced local bone erosion and systemic bone loss in CD46 Tg mice.

Research Products

• [Journal Article] Flesh-eating Streptococcus pyogenes triggers the expression of receptor activator of nuclear factor-kappaB ligand (2016)
  • Author(s): Matsui, H., Nakatani, Y., Yoshida, H., Takizawa, A., Takeuchi, O., Overby, A., Takahashi, T., Murayama, S. Y., Matsuo, K.
  • Journal Title: Cellular Microbiology Volume: 18 Issue: 10 Pages: 1-15
  • DOI: 10.1111/cmi.12581
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A highly susceptible CD46 transgenic mouse model of subcutaneous infection with Streptococcus dysgalactiae subspecies equisimilis. (2016)
  • Author(s): Haruno Yoshida, Tetsufumi Takahashi, Masahiko Nakamura, Anders Overby,Takashi Takahashi, Kimiko Ubukata, Hidenori Matsui
  • Journal Title: J Infection Chemother Volume: 22 Issue: 4 Pages: 229-234
  • DOI: 10.1016/j.jiac.2016.01.001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comparative genomics of mucoid and nonmucoid strains of Streptococcus pyogenes isolated from the same patient with streptococcal meningitis (2015)
  • Author(s): Haruno Yoshida, Yasuhito Ishigaki, Asako Takizawa, Kunihiko Moro, Yuki Kishi, Takashi Takahashi, Hidenori Matsui
  • Journal Title: Genome Announcements Volume: 3 Issue: 2
  • DOI: 10.1128/genomea.00221-15
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 溶血性連鎖球菌と化膿性関節炎 (2014)
  • Author(s): 高橋孝, 吉田春乃, 松井英則
  • Journal Title: Medical Practice Volume: 31 Pages: 147-147
• [Journal Article] 溶血性連鎖球菌と化膿性関節炎 (2014)
  • Author(s): 高橋 孝、吉田春乃、松井英則
  • Journal Title: Medical Practice Volume: 31 Pages: 147-147
• [Journal Article] Interleukin- 1β Response of Peritoneal Macrophages to Streptococcus pyogenes Exposure : Differential Response to Living and Heat- killed Bacteria (2013)
  • Author(s): Tokiyo Matoba, Yuriko Nakatani, Kazuaki Arai, Hidenori Matsui, Haruno Yoshida, Takashi Takahashi
  • Journal Title: Journal of Experimental &Clinical Medicine Volume: 5巻 Issue: 6 Pages: 227-230
  • DOI: 10.1016/j.jecm.2013.10.011
  • Peer Reviewed
• [Presentation] Hypervirulent GAS infection leads to systemic bone loss in a humanized mouse model (2016)
  • Author(s): 松井英則, 吉田春乃, 竹内修, 村山そう明
  • Organizer: 第89回日本細菌学会総会
  • Place of Presentation: 〒543-0001 大阪府大阪市天王寺区上本町８－２－６ 大阪国際交流センター
  • Year and Date: 2016-03-23
• [Presentation] GAS infection promotes a vicious cycle of bone loss through imbalanced bone remodeling (2015)
  • Author(s): Hidenori Matsui, Haruno Yoshida, Osamu Takeuchi, Somay. Y. Murayama
  • Organizer: 第88回日本細菌学会総会
  • Place of Presentation: 〒502-0817 岐阜市長良福光2695-2 長良川国際会議場
  • Year and Date: 2015-03-26 – 2015-03-28
• [Presentation] Gene conversion from a low-virulence to hypervirulence of S. pyogenes during Infection (2015)
  • Author(s): Haruno Yoshida, Hidenori Matsui
  • Organizer: 第88回日本細菌学会総会
  • Place of Presentation: 〒502-0817 岐阜市長良福光2695-2 長良川国際会議場
  • Year and Date: 2015-03-26 – 2015-03-28
• [Presentation] 感染時において、Osteoprotegerin (OPG)は骨だけではなく膵臓の保護にも貢献している (2014)
  • Author(s): 黒田有希子, 保田尚孝, 松井英則, 松尾光一
  • Organizer: 第32回日本骨代謝学会学術集会
  • Place of Presentation: 〒530-0005 大阪府大阪市北区中之島5-3-51 大阪国際会議場
  • Year and Date: 2014-07-24 – 2014-07-26
• [Presentation] CD46トランスジェニックマウスを用いた劇症型Ａ群レンサ球菌感染による骨破壊機構の解析 (2014)
  • Author(s): 松井英則, 吉田春乃, 高橋孝
  • Organizer: 第88回日本感染症学会学術集会・第62回日本化学療法学会総会 合同学会
  • Place of Presentation: 〒810-8650 福岡県福岡市 中央区地行浜2－2－3 ヒルトン福岡シーホーク
  • Year and Date: 2014-06-18 – 2014-06-20
• [Presentation] マクロライド耐性A群溶血性レンサ球菌における誘導型手リスロマイシン耐性検出の検討 (2014)
  • Author(s): 新井和明, 吉田春乃, 奥住倢子, 松井英則, 高橋孝
  • Organizer: 第88回日本感染症学会学術集会・第62回日本化学療法学会総会 合同学会
  • Place of Presentation: 〒810-8650 福岡県福岡市 中央区地行浜2－2－3 ヒルトン福岡シーホーク
  • Year and Date: 2014-06-18 – 2014-06-20
• [Presentation] CD46 Tg mouse model of osteoclastic bone resorption caused by s.c. infection with GAS (2014)
  • Author(s): Matsui, H., Yoshida, H., and Takeuchi, O.
  • Organizer: 第87回日本細菌学会総会
  • Place of Presentation: 東京都江戸川区（タワーホール船堀）
• [Presentation] Streptococcus pyogenes infection causes necrotizing fasciitis along with severe bone destruction promoted by receptor activator of nuclear factor B ligand (RANKL)-induced osteoclastogenesis in CD46 transgenic mice. (2013)
  • Author(s): Matsui, H., Takizawa, A., and Takeuchi, O.
  • Organizer: 第42会日本免疫学会学術集会
  • Place of Presentation: 千葉県千葉市（幕張メッセ）