EBV's pathogenicity through activation of innate immunity

• Project/Area Number: 19390129
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Virology
• Research Institution: Hokkaido University
• Principal Investigator: TAKADA KENZO Hokkaido University, 遺伝子病制御研究所, 教授 (30133721)
• Co-Investigator(Kenkyū-buntansha): 岩切 大 北海道大学, 遺伝子病制御研究所, 助教 (10307853) ; 瀬戸 絵理 北海道大学, 遺伝子病制御研究所, 学術研究員 (40431382)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥18,850,000 (Direct Cost: ¥14,500,000、Indirect Cost: ¥4,350,000); Fiscal Year 2008: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000); Fiscal Year 2007: ¥10,530,000 (Direct Cost: ¥8,100,000、Indirect Cost: ¥2,430,000)
• Keywords: 病原性 / EBウイルス / EBER / 自然免疫 / TLR-3 / 伝染性単核症 / 慢性活動性EBV感染症 / EBV関連血球貧食症候群 / EBV関連血球貪食症候群

Research Abstract

伝染性単核症、慢性活動性EBウイルス(EBV)感染症(CAEBV)、EBV関連血球貪食症候群(EBV-HLH)などの活動性のEBV感染症ではTNF-α、IL-6、IFN-γなどの炎症性サイトカインが大量に分泌され、サイトカインストームの状態を呈し、それが病態形成の主役を担っていると考えられる。我々は、EBVがコードする小RNA EBERがLaとの複合体の形で細胞外へ放出され、toll-like receptor 3(TLR-3)により二本鎖RNAとして検知され、インターフェロンや炎症性サイトカインの発現を誘導することを見出した。また、急性EBV感染症患者の血清中にTLR-3の活性化を誘導するに十分量のEBERが存在することも明らかにした。これらの知見は、何故EBVの急性感染症でサイトカインストームが引き起こされるのかを説明できる可能性がある。
本年度の研究では、EBERが樹状細胞の活性化を起こすか否かの検討を行った。ヒト末梢血より樹状細胞を分離し、in vitroで合成したEBERを培地中に加え、各種炎症性サイトカインの誘導をRT-PCR法、ELISA法により調べた。その結果、EBERが樹状細胞の活性化を引き起こすことが確認された。さらに、in vivoでのEBERの活性を調べるために、EBERトランスジェニックマウスを作製した。U6プロモーターに連結したEBER遺伝子を組み込んだマウスでEBERが発現することをin situ Hybridization法で確認した。今後、EBERトランスジェニックマウスでTLR3の活性化、炎症性サイトカインの誘導が起こるか否かを検討する予定である。

Research Products

• [Journal Article] Epstein-Barr virus nuclear protein EBNA3C residues critical for maintaining lymphoblastoid cell growth. Proc. (2009)
  • Author(s): Maruo, S., Wu, Y., Ito, M., Kieff, E.D. and Takada, K.
  • Journal Title: Natl. Acad. Sci. USA 106 Pages: 4419-4424
  • Peer Reviewed
• [Journal Article] Epstein-Barr virus nuclear protein EBNA3C residues critical for maintaining lymphoblastoid cell growth (2009)
  • Author(s): Maruo, S.
  • Journal Title: Proc. Natl. Acad. Sci. USA 106 Pages: 4419-4424
  • Peer Reviewed
• [Journal Article] Efficacy of Systemically administered mutant vesicular stomatitis virus(VSV{capital delta}51)combined with radiation for nasopharyngeal carcinoma. Clin (2008)
  • Author(s): Alajez, N.M., Mocanu, J.D., Shi, W., Chia, M.C., Alajez, N.M., Mocanu, J.D., Shi, W., Chia, M.C., Breitbach, C.J., Hui, A.B.Y., Knowles, S., Bell, J.C., Busson, P., Takada, K., Lo, K.-W., O'Sullivan, B., Gullane, P. and Liu, F.-F.
  • Journal Title: Cancer Res. 14 Pages: 4891-4897
  • Peer Reviewed
• [Journal Article] Epstein-Barr virus-encoded small RNA(EBER)induces IL-10 through RIG-I-mediated IRF-3 signaling. (2008)
  • Author(s): Samanta, M., Iwakiri, D. and Takada, K.
  • Journal Title: Oncogene 27 Pages: 4150-4160
  • Peer Reviewed
• [Journal Article] Survival advantage of EBV-associated gastric carcinoma : survivin up-regulation by viral latent membrane protein 2A (2008)
  • Author(s): Hino, R., Uozaki, H., Inoue, Y., Shintani, Y., Ushiki, T., Sakatani, T., Farrell, P.J., Takada, K. and Fukayama, M.
  • Journal Title: Cancer Res 68 Pages: 1427-1435
  • Peer Reviewed
• [Journal Article] Reconstitution of nasopharyngeal carcinoma-type Epstein-Barr virus infection induces tumorigenicity (2008)
  • Author(s): Seto, E., Ooka, T., Middeldorp, J. and Takada, K.
  • Journal Title: Cancer Res. 68 Pages: 1030-1036
  • Peer Reviewed
• [Journal Article] Reconstitution of nasopharyngeal carcinoma-type Epstein-Barr virus infection induces tumorigenicity (2008)
  • Author(s): Seto, E.
  • Journal Title: Cancer Res. 68 Pages: 1030-1036
  • Peer Reviewed
• [Journal Article] Epstein-Barr virus-encoded small RNA (EBER) induces IL-10 through RIG-I-mediated IRF-3 signaling (2008)
  • Author(s): Samanta, M.
  • Journal Title: Oncogene 27 Pages: 4150-4160
  • Peer Reviewed
• [Journal Article] Reconstitution of nasopharyngeal carcinoma-type Epstein-Barr virus infection induces tumorigenicity. (2008)
  • Author(s): Seto, E.
  • Journal Title: Cancer Res. 68 Pages: 1030-1036
  • Peer Reviewed
• [Journal Article] Epstein-Barr virus(EBV)-encoded RNA 2(EBER2)but not EBER1 plays a critical role in EBV-induced B-cell growth transformation (2007)
  • Author(s): Wu, Y., Maruo, S., Yajima, M., Kanda, T. and Takada, K.
  • Journal Title: J. Virol 81 Pages: 11236-11245
  • Peer Reviewed
• [Journal Article] Symmetrical localization of extrachromosomally-replicating viral episomes on sister chromatids (2007)
  • Author(s): Kanda, T., Kamiya, M., Maruo, S., Iwakiri, D. and Takada, K.
  • Journal Title: J. Cell Sci 120 Pages: 1529-1539
  • Peer Reviewed
• [Journal Article] Epstein-Barr virus BZLF1 gene, a switch from latency to lytic infection, is expressed as an immediate early gene following primary infection of B-lymphocytes (2007)
  • Author(s): Wen, W., Iwakiri, D., Yamamoto, K., Maruo, S., Kanda, T. and Takada, K.
  • Journal Title: J. Virol 81 Pages: 1037-1042
  • Peer Reviewed
• [Journal Article] Epstein-Barr virus(EBV)-encoded RNA2(EBER2)but not EBER1 plays a critical role in EBV-induced B-cell growth transformation. (2007)
  • Author(s): Wu, Y
  • Journal Title: J. Virol. 81 Pages: 11236-11245
  • Peer Reviewed
• [Journal Article] Endoplasmic reticulum stress triggers XBP-1-mediated upregulation of an EBV oncoprotein in nasopharyngeal carcinoma
  • Author(s): Hsiao, J.R, Chang, K.C., Chen, C.W., Wu, S.Y., Hsu, M.C., Jin, Y.T., Tsai, S.T., Takada, K. and Chang, Y.
  • Journal Title: Cancer Res. (in press)
  • Peer Reviewed
• [Journal Article] Viral protein LMP2A induces STAT3/DNMT1-mediated promoter methylation of the PTEN gene in EBV-associated gastric carcinoma
  • Author(s): Hino, R., Uozaki, H., Murakami, N., Ushiki, T., Shinozaki, A., Ishikawa, S., Morikawa, T., Nakaya, T., Sakatani, T., Takada, K. and Fukayama, M.
  • Journal Title: Cancer Res. (in press)
  • Peer Reviewed
• [Journal Article] Epstein-Barr virus-encoded small RNA(EBER)induces IL-10 through RIG-I-mediated IRF-3 signaling.
  • Author(s): Samanta, M.
  • Journal Title: Oncogene (In press)
  • Peer Reviewed
• [Presentation] Epstein-Barr virus-induced oncogenesis through utilizing the innate immunity system (2008)
  • Author(s): Takada, K., Iwakiri, D. and M. Samanta
  • Organizer: 13th Biennial Conference of the International Association for Research on Epstein-Barr Virus and Associated Diseases
  • Place of Presentation: Guangzhou
  • Year and Date: 2008-11-08
• [Presentation] Activation of innate immunity by Epstein-Barr virus-encoded non-coding RNA and oncogenesis (2007)
  • Author(s): Takada, K.
  • Organizer: 3rd Symposium of High Technology Research Center.
  • Place of Presentation: Chiba
  • Year and Date: 2007-11-16
• [Presentation] EBV-encoded non-coding RNA exerts oncogenic activity by utilizing the innate immunity system. (2007)
  • Author(s): Takada, K
  • Organizer: 13rd International Conference on Immunobiology and Prophylaxis of Human Herpesvirus Infections
  • Place of Presentation: Palazzo del Popolo Orvieto, Italy
  • Year and Date: 2007-11-06
• [Presentation] EBV-encoded non-coding RNA exerts oncogenic activity by utilizing the innate immunity system (2007)
  • Author(s): Takada, K.
  • Organizer: 13rd International Conference on Immunobiology and Prophylaxis of Human Herpesvirus Infections
  • Place of Presentation: Orvieto, Italy
  • Year and Date: 2007-11-05
• [Presentation] Role of Epstein-Barr virus-encoded non-coding RNAs and innate immunity in oncogenesis (2007)
  • Author(s): Takada, K. and Iwakiri, D.
  • Organizer: 第66回日本癌学会学術総会シンポジウム「ウイルス発がん」
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-03
• [Presentation] Role of Epstein-Barr virus-encoded non-coding RNAs and innate immunity in oncogenesis (2007)
  • Author(s): Takada, K., Samanta, M., Iwakiri, D., Wu, Y. and Maruo, S.
  • Organizer: East-West Symposium on Nasopharyngeal Carcinoma. Sunshine Coast
  • Place of Presentation: Australia
  • Year and Date: 2007-08-02
• [Book] 南江堂、東京 (2009)
  • Author(s): 高田賢蔵(編集)
  • Publisher: 医科ウイルス学(第3版)
• [Book] 診断と治療社、東京 (2008)
  • Author(s): 高田賢蔵(監修)
  • Publisher: EBウイルス(第3版)
• [Book] EBウイルス感染の概要「EBウイルス」第2版 (2008)
  • Author(s): 高田賢蔵
  • Total Pages: 3
  • Publisher: 診断と治療社