Investigation of Clostridium perfringens alpha-toxin receptor: focus on gangliosides

• Project/Area Number: 24590542
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Bacteriology (including Mycology)
• Research Institution: Niigata University (2013-2014); Tokushima Bunri University (2012)
• Principal Investigator: ODA MASATAKA 新潟大学, 医歯学系, 准教授 (00412403)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: ウエルシュ菌 / α毒素 / ガングリオシド / GM1a / チロシンキナーゼ / TrkA受容体 / ホスホリパーゼC-γ1 / 細胞膜流動性 / ホスホリパーゼC / ジアシルグリセロール / TrkA / クラスター / ノックアウトマウス / サイトカイン

Outline of Final Research Achievements

We investigated the receptor of Clostridium perfringens alpha-toxin, which is main factor of gas gangrene. First, we revealed that Trp-84 and Tyr-85 in the loop region in the N-domain of alpha-toxin specifically interact with ganglioside GM1a through a carbohydrate moiety, leading to the clustering of GM1a at the cell membrane and activation of tyrosine kinase receptor (TrkA). Second, we discovered that alpha-toxin also specifically activated endogenous phospholipase Cγ-1, a TrkA adaptor protein, via phosphorylation. Third, the flip-flop motion of hydrophobic lipids such as diacylglycerol in the cells treated with the toxin leads to the accumulation of GM1a and TrkA.

Research Products

• [Journal Article] Clostridium perfringens alpha-toxin induces GM1a clustering and TrkA phosphorylation in the host cell membrane. (2015)
  • Author(s): Takagishi, T., Oda, M., Kabura, M., Kurosawa, M., Tominaga, K., Urano, S., Ueda, Y.,Kobayashi, K., Kobayashi, T., Sakurai, J., Terao, Y., and Nagahama, M.
  • Journal Title: PLoS one Volume: 10 Issue: 4 Pages: e0120497-e0120497
  • DOI: 10.1371/journal.pone.0120497
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Recent insights into Clostridium perfringens beta-toxin. (2015)
  • Author(s): Nagahama, M., Ochi, S., Oda, M., Miyamoto, K., Takehara, M., and Kobayashi, K.
  • Journal Title: Toxins Volume: 7 Issue: 2 Pages: 396-406
  • DOI: 10.3390/toxins7020396
  • Peer Reviewed / Open Access
• [Journal Article] Tetranorsesquiterpenoids and Santalane-type Sesquiterpenoids from Illicium lanceolatum and Their Antimicrobial Activity against the Oral Pathogen Porphyromonas gingivalis. (2015)
  • Author(s): Kubo, M., Nishikawa, Y., Harada, K., Oda, M., Huang, JM., Domon, H., Terao, Y., and Fukuyama, Y.
  • Journal Title: J. Nat. Prod. Volume: in press
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Identification of the replication region in pBCNF5603, a bacteriocin-encoding plasmid, in the enterotoxigenicClostridium perfringens strain F5603. (2015)
  • Author(s): Miyamoto, K., Seike, S., Takagishi, T., Okui, K., Oda, M., Takehara, M., Nagahama, M.
  • Journal Title: BMC Microbiology Volume: in press
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Vizantin inhibits endotoxin-mediated immune responses via the Toll-like receptor 4/MD-2 complex. (2014)
  • Author(s): Oda, M., Yamamoto, H., Shibutani, M., Nakano, M., Yabiku, K., Tarui, T., Kameyama, N., Shirakawa, D., Obayashi, S., Watanabe, N., Nakase, H., Suenaga, M., Matsunaga, Y., Nagahama, M., Takahashi, H., Imagawa, H., Kurosawa, M., Terao, Y., Nishizawa, M., and Sakurai, J.
  • Journal Title: Journal of Immunology Volume: 193 Issue: 9 Pages: 4507-4514
  • DOI: 10.4049/jimmunol.1401796
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Phospholipase C produced by Clostridium botulinum types C and D: comparison of gene, enzymatic, and biological activities with those of Clostridium perfringens alpha-toxin. (2013)
  • Author(s): Fatmawati, N.N.D., Sakaguchi, Y., Suzuki, T., Oda, M., Shimizu, K., Yamamoto, Y., Sakurai, J., Matsushita, O., Oguma, K
  • Journal Title: Acta Med. Okayama Volume: 67 Pages: 9-18
  • Peer Reviewed
• [Journal Article] Development of vizantin, a safe immunostimulant, based on the structure－activity relationship of trehalose-6,6′-dicorynomycolate (2013)
  • Author(s): H. Yamamoto, M. Oda, M. Nakano, N. Watanabe, K. Yabiku, M. Shibutani, M. Inoue, H. Imagawa, M. Nagahama, S. Himeno, K. Setsu, J. Sakurai, M. Nishizawa
  • Journal Title: J. Med. Chem Volume: 56 Issue: 1 Pages: 381-385
  • DOI: 10.1021/jm3016443
  • Peer Reviewed
• [Journal Article] Bacillus cereus sphingomyelinase recognizes ganglioside GM3. (2013)
  • Author(s): Oda, M., Fujita, A., Okui, K., Miyamoto, K., Shibutani, M., Takagishi, T., Kobayashi, K., Nagahama, M.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 431 Issue: 2 Pages: 164-168
  • DOI: 10.1016/j.bbrc.2013.01.002
  • Peer Reviewed
• [Journal Article] Arginine ADP-ribosylation Mechanism Based on Structural Snapshots of Iota-toxin and Actin Complex. (2013)
  • Author(s): Tsurumura, T., Tsumori, Y., Qiu, H., Oda, M., Sakurai, J., Nagahama, M., Tsuge, H.
  • Journal Title: Proc. Natl. Acad. Sci. U S A. Volume: 110 Issue: 11 Pages: 4267-4272
  • DOI: 10.1073/pnas.1217227110
  • Peer Reviewed
• [Journal Article] Concise Synthesis of a Probe Molecule Enabling Analysis and Imaging of Vizantin. (2013)
  • Author(s): Yamamoto, H., Oda, M., Nakano, M., Watanabe, N., Yabiku, K., Shibutani, M., Nakanishi, T., Suenaga, M., Inoue, M., Imagawa, H., Nagahama, M., Matsunaga, Y., Himeno, S., Setsu, K., Sakurai, J., Nishizawa, M.
  • Journal Title: Chem. Pharm. Bull. Volume: 61 Pages: 452-459
  • NAID: 130003360757
  • Peer Reviewed
• [Journal Article] A recombinant carboxy-terminal domain of alpha-toxin protects mice against Clostridium perfringens. (2013)
  • Author(s): Nagahama M, Oda M, Kobayashi K, Ochi S, Takagishi T, Shibutani M, Sakurai J
  • Journal Title: Microbiol. Immunol. Volume: 57(5) Issue: 5 Pages: 340-345
  • DOI: 10.1111/1348-0421.12036
  • NAID: 40019653245
  • Peer Reviewed
• [Journal Article] Computational module assembled from different protease family motifs identifiesPI PLC from Bacillus cereus as a putative prolyl peptidase having a serine protease scaffold. (2013)
  • Author(s): Ramirez, A.R., Shukla, M., Oda, M., Chakraborty, S., Minda, R., Asgeirsson, B., Goni, FM., Rao, BJ.
  • Journal Title: PLoS one Volume: 8 Issue: 8 Pages: e70923-e70923
  • DOI: 10.1371/journal.pone.0070923
  • Peer Reviewed
• [Journal Article] The p38 MAPK and JNK pathways protect host cells against Clostridium perfringens beta-toxin. (2013)
  • Author(s): Nagahama M, Shibutani M, Seike S, Yonezaki M, Takagishi T, Oda M, Kobayashi K, Sakurai J
  • Journal Title: Infect. Immun. Volume: 81(10) Issue: 10 Pages: 3703-3708
  • DOI: 10.1128/iai.00579-13
  • Peer Reviewed
• [Journal Article] Dipeptidyl peptidase-IV inhibitors used in type-2 diabetes inhibit a phospholipase C: a case of promiscuous scaffolds in proteins. (2013)
  • Author(s): Chakraborty, S., Rendon-Ramirez, A., Asgeirsson, B., Dutta, M., Ghosh, A., Oda, M., Venkatramani, R., Rao, B., Dandekar, A., Goni, F.
  • Journal Title: F1000Research Volume: 2 Pages: 286-286
  • DOI: 10.12688/f1000research.2-286.v1
  • Peer Reviewed
• [Journal Article] Clostridium perfringens alpha-toxin recognizes the GM1a/TrkA complex. (2012)
  • Author(s): Oda, M., Kabura, M., Takagishi, T., Suzue, A., Tominaga, K., Urano, S., Nagahama, M., Kobayashi, K., Furukawa, K., Furukawa, K., Sakurai, J.
  • Journal Title: J. Biol. Chem. Volume: 287 Pages: 33070-33079
  • Peer Reviewed
• [Journal Article] Clostridium perfringens alpha-toxin induces the release of IL-8 through a dual pathway via TrkA in A549 cells. (2012)
  • Author(s): Oda, M., Shiihara, R., Ohmae, Y., Kabura, M., Takagishi, T, Kobayashi, K., Nagahama, M., Inoue, M., Abe, T., Setsu, K., Sakurai, J.
  • Journal Title: Biophys. Biochim. Acta - Molecular Basis of Disease Volume: 1822 Pages: 1581-1589
  • Peer Reviewed
• [Presentation] Streptococcus pyogenes CAMP factorのRAW264.7細胞に対する病原性解析 (2015)
  • Author(s): 黒澤美絵，小田真隆，土門久哲，寺尾豊
  • Organizer: 第88回日本細菌学会総会
  • Place of Presentation: 長良川国際会議場
  • Year and Date: 2015-03-26 – 2015-03-28
• [Presentation] ウエルシュ菌ε毒素のオリゴマー形成におけるセラミドの役割 (2015)
  • Author(s): 高松輝美，高岸照久，小田真隆，小林敬子，竹原正也，永浜政博
  • Organizer: 第88回日本細菌学会総会
  • Place of Presentation: 長良川国際会議場
  • Year and Date: 2015-03-26 – 2015-03-28
• [Presentation] ウエルシュ菌α毒素の脂質クラスター形成に対する内因性PLC-γ1の役割 (2015)
  • Author(s): 高岸照久，小田真隆，竹原正也，小林敬子，永浜政博
  • Organizer: 第88回日本細菌学会総会
  • Place of Presentation: 長良川国際会議場
  • Year and Date: 2015-03-25 – 2015-03-28
• [Presentation] Streptococcus mutansバイオフィルムに対する植物由来抽出物の検索 (2014)
  • Author(s): 坂上雄樹，土門久哲，小田真隆，興地隆史，寺尾豊
  • Organizer: 第51回日本細菌学会中部支部総会
  • Place of Presentation: 北陸大学薬学部
  • Year and Date: 2014-10-17 – 2014-10-18
• [Presentation] Streptococcous pyogenes CAMP factorの免疫担当細胞に対する病原性解析 (2014)
  • Author(s): 黒澤美絵，小田真隆，土門久哲，寺尾 豊
  • Organizer: 第51回日本細菌学会中部支部総会
  • Place of Presentation: 北陸大学薬学部
  • Year and Date: 2014-10-17 – 2014-10-18
• [Presentation] 多機能性糖脂質の自然免疫活性化メカニズムの解明 (2014)
  • Author(s): 小田真隆，山本博文，黒澤美絵，土門久哲，寺尾 豊
  • Organizer: 第51回日本細菌学会中部支部総会
  • Place of Presentation: 北陸大学薬学部
  • Year and Date: 2014-10-17 – 2014-10-18
• [Presentation] 慢性炎症性疾患におけるT L R シグナル抑制因子の解析 (2014)
  • Author(s): 土門久哲，坂上雄樹，小田真隆，寺尾豊
  • Organizer: 第51回日本細菌学会中部支部総会
  • Place of Presentation: 北陸大学薬学部
  • Year and Date: 2014-10-17 – 2014-10-18
• [Presentation] A群レンサ球菌CAMPファクターのマクロファージに対する病原性解析 (2014)
  • Author(s): 小田真隆，黒澤美絵，土門久哲，寺尾豊
  • Organizer: 第56回歯科基礎医学会学術大会・総会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] 歯周炎におけるTLR シグナル抑制因子の解析 (2014)
  • Author(s): 土門久哲，小田真隆，寺尾豊
  • Organizer: 第56回歯科基礎医学会学術大会・総会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] 合成糖脂質のStreptococcus mutansバイオフィルムに対する作用 (2014)
  • Author(s): 黒澤美絵，小田真隆，土門久哲，寺尾豊
  • Organizer: 第56回歯科基礎医学会学術大会・総会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Streptococcus mutansに対する植物由来抽出物の殺菌ならびに抗バイオフィルム効果の検討 (2014)
  • Author(s): 坂上雄樹，土門久哲，小田真隆，興地隆史，寺尾豊
  • Organizer: 第56回歯科基礎医学会学術大会・総会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] 研究のツキと運を呼び込むために (2014)
  • Author(s): 小田真隆
  • Organizer: 第87回日本細菌学会総会
  • Place of Presentation: 東京都、船堀タワーホール
  • Invited
• [Presentation] ウエルシュ菌ε毒素のオリゴマー形成における中性スフィンゴミエリナーゼの関与 (2014)
  • Author(s): 高岸照久、小田真隆、永浜政博
  • Organizer: 第87回日本細菌学会総会
  • Place of Presentation: 東京都、船堀タワーホール
• [Presentation] 敗血症患者由来セレウス菌の病原性発現とスフィンゴミエリナーゼの関係 (2013)
  • Author(s): 小田真隆、櫻井純、永浜政博
  • Organizer: トキシンシンポジウム
  • Place of Presentation: 兵庫県、楓香荘
  • Invited
• [Presentation] ウエルシュ菌α毒素の病原性発現 におけるGM1a/TrkA複合体の役割 (2013)
  • Author(s): 小田真隆
  • Organizer: 第66 回日本細菌学会中国・四国支部総会
  • Place of Presentation: 広島県、広島国際大学
  • Invited
• [Presentation] ウエルシュ菌α毒素の毒性発現におけるガングリオシドGM1a の役割 (2012)
  • Author(s): 小田真隆、高岸照久、渋谷昌弘、鈴江綾佳、小林敬子、櫻井純、永浜政博
  • Organizer: 第65回日本細菌学会中国・四国支部総会
  • Place of Presentation: 徳島大学
• [Presentation] ウエルシュ菌α毒素とTrkA/GM1aとの相互作用の解析 (2012)
  • Author(s): 高岸照久、小田真隆、蕪道子、鈴江綾佳、小林敬子、櫻井純、永浜政博
  • Organizer: 第51回日本薬学会・日本薬剤師会・日本病院薬剤師会・中国四国支部学術大会
  • Place of Presentation: 島根県 サンラポーむらくも
• [Presentation] ガス壊疽毒素の巧みな毒性発現メカニズム
  • Author(s): 小田真隆
  • Organizer: 宮崎大学医学部 IR推進機構特別講演
  • Place of Presentation: 宮崎大学医学部
  • Invited
• [Presentation] ガス壊疽毒素の受容体探索 ☆光を灯した糖脂質糖鎖固定化アレイ☆
  • Author(s): 小田真隆
  • Organizer: 日本糖質学会総会-招待講演
  • Place of Presentation: 鹿児島県 市民文化ホール
  • Invited
• [Book] Molecular Medical Microbiology-Second edition (2014)
  • Author(s): Nagahama M, Oda M, Tsuge H., Kobayashi K.: Enteric toxins of Clostridium perfringens
  • Total Pages: 2216
  • Publisher: Elsevier
• [Remarks] 新潟大学 大学院医歯学総合研究科 微生物感染症学分野
  • URL: http://www.dent.niigata-u.ac.jp/microbio/microbio.html