Identification of meningococcal virulence factors and the expression profile by using clinical isolates

• Project/Area Number: 15K08485
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Bacteriology (including mycology)
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: Takahashi Hideyuki 国立感染症研究所, 細菌第一部, 主任研究官 (60321866)
• Co-Investigator(Renkei-kenkyūsha): YANAGISAWA Tatsuo 理化学研究所, 横山構造生物学研究室, 研究員 (10450420)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 髄膜炎菌 / 病原性 / 感染 / ヒト / 細胞内 / システイン / ヒト培養細胞 / グルタチオン / ヒト脳血管内皮細胞 / アミノ酸 / 臨床分離株 / 莢膜多糖体合成遺伝子 / 脳血管内皮細胞

Outline of Final Research Achievements

I selected 20 clinical meningococcal strains isolated from patients and healthy carriers, respectively. After comparing the infectious abilities to Human Brain Microvascular Endothelial Cells (HBMEC) in vitro, I further selected 9 high and low infecious strains from the 20 strains, respectively. Furthermore, the expression profile of outer membrane proteins within clinical isolates by Tandem Mass Tag (TMT) labeling system. With comparison with the infectious abilities to HBMEC, a protein named cysteine binding protein (Cbp), which is one of the components of a cysteine transporter system in N. meningitidis was found to be related to the meningococcal pathogenesis. Further analyses revealed that meningococcal cysteine uptake via Ctp system was essential for intracellular survival and sustaining in the host cells and played as a meningococcal nutrient virulent factor in N. meningitidis.

Research Products

• [Int'l Joint Research] Johns Hopkins University(米国)
• [Int'l Joint Research] John Hopkins University(米国)
• [Journal Article] Structural basis of protein arginine rhamnosylation by glycosyltransferase EarP (2018)
  • Author(s): Sengoku Toru、Suzuki Takehiro、Dohmae Naoshi、Watanabe Chiduru、Honma Teruki、Hikida Yasushi、Yamaguchi Yoshiki、Takahashi Hideyuki、Yokoyama Shigeyuki、Yanagisawa Tatsuo
  • Journal Title: Nature Chemical Biology Volume: 14 Issue: 4 Pages: 368-374
  • DOI: 10.1038/s41589-018-0002-y
  • Peer Reviewed
• [Journal Article] Invasive meningococcal disease due to ciprofloxacin-resistant Neisseria meningitidis sequence type 4821: the first case in Japan. (2018)
  • Author(s): Yu Kawasaki, Kousaku Matsubara, Hideyuki Takahashi, Masatomo Morita, Makoto Ohnishi, Masayuki Hori, Kenichi Isome, Aya Iwata, Hiroyuki Nigami, Go Yamamoto, Kiyofumi Ohkusu.
  • Journal Title: Journal of Infection and Chemotherapy Volume: 24 Issue: 4 Pages: 305-308
  • DOI: 10.1016/j.jiac.2017.11.001
  • Peer Reviewed
• [Journal Article] Meningococcal meningitis with neurological complications and meningococcemia due to serogroup W sequence type 11 complex. (2018)
  • Author(s): Nobuaki Mori, Tomofumi Hayashi, Hideki Nakamura, Hideyuki Takahashi.
  • Journal Title: Journal of Infection and Chemotherapy Volume: 24 Issue: 5 Pages: 398-400
  • DOI: 10.1016/j.jiac.2017.12.005
  • Peer Reviewed
• [Journal Article] Meningococcal disease outbreak related to the World Scout Jamboree in Japan, 2015. (2017)
  • Author(s): Kanai M, Kamiya H, Smith-Palmer A, Takahashi H, Hachisu Y, Fukusumi M, et al.
  • Journal Title: Western pacific Surveillance and Response Volume: 8 Issue: 2 Pages: 1-6
  • DOI: 10.5365/wpsar.2016.7.3.007
  • Peer Reviewed
• [Journal Article] Genomic characterization of urethritis-associated Neisseria meningitidis shows that a wide range of N. meningitidis strains can cause urethritis. (2017)
  • Author(s): Kevin Ma, Magnus Unemo, Samo Jeverica, Bob Kirkcaldy, Hideyuki Takahashi, Makoto Ohnishi, and Yonatan Grad
  • Journal Title: Journal of Clinical Microbiology Volume: 55 Issue: 12 Pages: 3374-3383
  • DOI: 10.1128/jcm.01018-17
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] National surveillance for meningococcal disease in Japan (2016)
  • Author(s): Fukusumi M, Kamiya H, Takahashi H, Kanai M, Hachisu Y, Saitoh T, Ohnishi M, Oishi K, Sunagawa T.
  • Journal Title: Vaccine Volume: 34 Pages: 4068-4071
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Novel Loop-Mediated Isothermal Amplification Assay for Serogroup Identification of Neisseria meningitidis in Cerebrospinal Fluid (2016)
  • Author(s): Lee DK, Kim EJ, Kilgore P, Takahashi H, Ohnishi M, Tomono J, Miyamoto S, Omagari D, Kim DW and Seki M.
  • Journal Title: Frontiers in Microbiology Volume: 6 Pages: 1548-1548
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Neisseria meningitidis Translation Elongation Factor P and Its Active-Site Arginine Residue Are Essential for Cell Viability (2016)
  • Author(s): Yanagisawa T, Takahashi H, Suzuki T, Masuda A, Dohmae N, Yokoyama S.
  • Journal Title: PLoS ONE Volume: 11(2) Issue: 2 Pages: e0147907-e0147907
  • DOI: 10.1371/journal.pone.0147907
  • Peer Reviewed / Open Access
• [Journal Article] Meningococcal carriage rates in healthy individuals in Japan determined using Loop-Mediated Isothermal Amplification and oral throat wash specimens. (2016)
  • Author(s): Takahashi H, Haga M, Sunagawa T, Saitoh T, Kitahara T, Matsumoto S, Ohnishi M.
  • Journal Title: J Infect Chemotherapy Volume: 22 Pages: 501-504
  • Open Access
• [Journal Article] A Novel Loop-Mediated Isothermal Amplification Assay for Serogroup Identification of Neisseria meningitidis in Cerebrospinal Fluid. (2016)
  • Author(s): Do Kyung Lee1, Eun Jin Kim, PaulE Kilgore, Hideyuki Takahashi, Makoto Ohnishi, Jun Tomono, Shigehiko Miyamoto, Daisuke Omagari, Dong Wook Kim and Mitsuko Seki.
  • Journal Title: Frontiers in Microbiology Volume: 6 Pages: 1548-1548
  • DOI: 10.3389/fmicb.2015.01548
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Multiple Functions of Glutamate Uptake via Meningococcal GltT-GltM L-Glutamate ABC Transporter in Neisseria meningitidis Internalization into Human Brain Microvascular Endothelial Cells. (2015)
  • Author(s): Takahashi H, Yanagisawa T, Kim KS, Yokoyama S, Ohnishi M.
  • Journal Title: Infection and Immunity Volume: 83 Issue: 9 Pages: 35553567-35553567
  • DOI: 10.1128/iai.00654-15
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Clinical Evaluation of a Loop-Mediated Isothermal Amplification (LAMP) Assay for Rapid Detection of Neisseria meningitidis in Cerebrospinal Fluid. (2015)
  • Author(s): DoKyung Lee, Eun Jin Kim, Paul E. Kilgore, Soon Ae Kim, Hideyuki Takahashi, Makoto Ohnishi, Dang Duc Anh, Bai Qing Dong, Jung Soo Kim, Jun Tomono, Shigehiko Miyamoto, Tsugunori Notomi, Dong Wook Kim, Mitsuko Seki.
  • Journal Title: Plos One Volume: 10 Issue: 4 Pages: e0122922-e0122922
  • DOI: 10.1371/journal.pone.0122922
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] 臨床分離株の宿主細胞への侵襲能と細胞外因子の発現量の相互比較による髄膜炎菌の病原性因子の探索及び解析 (2018)
  • Author(s): 高橋 英之、柳沢 達男、横山 茂之
  • Organizer: 第90回日本細菌学会総会
• [Presentation] 咽頭うがい液を用いた髄膜炎菌の健康者保菌調査の実施 (2017)
  • Author(s): 高橋英之、羽賀將衛、砂川富正、齋藤剛仁、北原武尊、松本壮吉、大西真
  • Organizer: 日本細菌学会総会
  • Place of Presentation: 仙台市
  • Year and Date: 2017-03-19
• [Presentation] 髄膜炎菌由来の翻訳因子EF-Pのラムノース修飾による活性化の構造的基盤 (2017)
  • Author(s): 仙石 徹、鈴木 健裕、堂前 直、渡邉 千鶴、本間 光貴、疋田 泰士、山口 芳樹、高橋 英之、横山 茂之、柳沢 達男
  • Organizer: ComBio2017
• [Presentation] 反転型糖鎖転移酵素によるタンパク質アルギニン・ラムノシル化の構造基盤 (2017)
  • Author(s): 仙石 徹、鈴木 健裕、堂前 直、渡邉 千鶴、本間 光貴、疋田 泰士、山口 芳樹、高橋 英之、柳沢 達男、横山 茂之
  • Organizer: ComBio2017
• [Presentation] Multiple functions of glutamate uptake via meningococcal GltT-GltM L-glutamate ABC transporter for Neisseria meningitidis internalization into human brain microvascular endothelial cells. (2016)
  • Author(s): Hideyuki Takahashi, Tatsuo Yanagisawa, Kwang Sik Kim, Shigeyuki Yokoyama and Makoto Ohnishi.
  • Organizer: International Pathogenic Neisseria Conference
  • Place of Presentation: Manchester UK
  • Year and Date: 2016-09-05
  • Int'l Joint Research
• [Presentation] 侵襲性髄膜炎菌感染症の世界及び国内の実態 (2016)
  • Author(s): 高橋英之
  • Organizer: 日本細菌学会
  • Place of Presentation: 大阪国際交流センター
  • Year and Date: 2016-03-23
  • Int'l Joint Research
• [Book] 髄膜炎菌 日常診断に役立つ小児感染症マニュアル (2017)
  • Author(s): 高橋英之、大西真
  • Total Pages: 6
  • Publisher: 日本小児感染症学会
• [Book] 侵襲性髄膜炎菌性感染症の現状と基礎知識 (2017)
  • Author(s): 高橋英之
  • Total Pages: 1
  • Publisher: 少年写真新聞
• [Book] 髄膜炎菌による感染症、中学保健ニュース (2017)
  • Author(s): 高橋英之
  • Total Pages: 1
  • Publisher: 少年写真新聞
• [Book] 髄膜炎菌感染症 (2016)
  • Author(s): 高橋英之、大西真
  • Total Pages: 6
  • Publisher: 金原出版株式会社
• [Book] 髄膜炎菌性髄膜炎（侵襲性髄膜炎菌感染症） (2015)
  • Author(s): 体と心 保健総合大百科 小学校編
  • Total Pages: 3
  • Publisher: 少年写真新聞社
• [Book] 髄膜炎菌性髄膜炎（侵襲性髄膜炎菌感染症） (2015)
  • Author(s): 体と心 保健総合大百科 中・高校編
  • Total Pages: 3
  • Publisher: 少年写真新聞社