Disruption of innate immune response by hepatitis C virus

• Project/Area Number: 19790340
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Virology
• Research Institution: Okayama University
• Principal Investigator: DANSAKO Hiromichi Okayama University, 大学院・医歯薬学総合研究科, 助教 (80379841)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥3,650,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥450,000); Fiscal Year 2008: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2007: ¥1,700,000 (Direct Cost: ¥1,700,000)
• Keywords: 分子 / 細胞 / 病原性 / 感染防御・ワクチン / C型肝炎ウイルス / 自然免疫 / 二本鎖RNA / IFN-beta / NS5B / IRF-3 / TRAF 6 / RIG-I / 持続感染 / インターフェロン-β / TLR3 / TRIF経路 / RIG-1 / MDA5経路 / NS3-4A蛋白質 / NF-kB / 肝発がん

Research Abstract

C型肝炎ウイルス(HCV)による自然免疫システムの撹乱機構の解明を目的として行った研究において、以下のような成果を得た。(1)従来の報告とは異なり、NS3-4A蛋白質はTRIF蛋白質を切断しておらず、自然免疫機構の抑制はRIG-I/IPS-1経路に限定されていた。(2)NS5B蛋白質によるIFN-βの産生はTLR3経路およびRIG-I/MDA5経路の活性化、さらには両経路の下流の転写因子IRF-3の活性化を経て誘導されていた。(3)NS5B蛋白質によるIFN-βの産生誘導はTRAF3やTRAF6のノックダウンにより亢進することを示した。また、活性化されたIRF-3の調節にTRAF6が関与している可能性が示唆された。(4)PH5CH8細胞において、NS5Bは二本鎖RNAを産生していることを示した。これらの研究成果により、HCVはこれら分子との相互作用により自然免疫システムを撹乱している可能性が示唆された。

Research Products

• [Journal Article] A new living cell-based assay system for monitoring genome-length hepatitis C virus RNA replication (2008)
  • Author(s): H. Dansako, M. Ikeda, K. Abe, K. Mori, K. Takemoto, Y. Ariumi, and N. Kato
  • Journal Title: Virus Res 137 Pages: 72-79
  • Peer Reviewed
• [Journal Article] ATM, a DNA damage sensor, is required for hepatitis C virus RNA replication (2008)
  • Author(s): Y. Ariumi, M. Kuroki, H. Dansako, K. Abe, M. Ikeda, T. Wakita, and N. Kato
  • Journal Title: J Virol 82 Pages: 9639-9646
  • Peer Reviewed
• [Journal Article] New efficient replication system with hepatitis C virus genome derived from a patient with acute hepatitis C (2008)
  • Author(s): K. Mori, K. Abe, H. Dansako, Y. Ariumi, M. Ikeda, and N. Kato
  • Journal Title: Biochem Biophys Res Commun 371 Pages: 104-109
  • Peer Reviewed
• [Journal Article] A new living cell-based assay system for monitoring genome-length hepatitis C virus RNA replication (2008)
  • Author(s): Hiromichi Dansako
  • Journal Title: Virus Research 137 Pages: 72-79
  • Peer Reviewed
• [Journal Article] The DNA damage sensors ataxia-telangiectasia mutated kinase and checkpoint kinase 2 are required for hepatitis C virus RNA replication (2008)
  • Author(s): Yasuo Ariumi
  • Journal Title: Journal of Virology 82 Pages: 9639-9646
  • Peer Reviewed
• [Journal Article] New efficient replication system with hepatitis C virus genome derived from a patient with acute hepatitis C (2008)
  • Author(s): Kyoko Mori
  • Journal Title: Biochemical and Biophysical Research Communications 371 Pages: 104-109
  • Peer Reviewed
• [Journal Article] Limited suppression of the interferon-beta production by hepatitis C virus serine procultured human hepatocytes (2007)
  • Author(s): H. Dansako, M. Ikeda, and N. Kato
  • Journal Title: FEBS J. 274 Pages: 4161-4176
  • Peer Reviewed
• [Journal Article] Comprehensive analysis of the effects of ordinary nutrients on hepatitis C virus RNA replication in cell culture (2007)
  • Author(s): M. Yano, M. Ikeda, K. Abe, H. Dansako, S. Ohkoshi, Y. Aoyagi, and N. Kato
  • Journal Title: Antimicrob Agents Chemother 51 Pages: 2016-2027
  • Peer Reviewed
• [Journal Article] DDX3 DEAD-box RNA helicase irequired for hepatitis C virus RNA replication (2007)
  • Author(s): Y. Ariumi, M. Kuroki, K. Abe, H. Dansako, M. Ikeda, T. Wakita, and N. Kato
  • Journal Title: J Virol 81 Pages: 13922-13926
  • Peer Reviewed
• [Journal Article] Limted suppression of the interon-β production by hepatitis C cirus serine protease in cultured human hepatocytes (2007)
  • Author(s): Hiromichi Dansako
  • Journal Title: FEBS Journal 274 Pages: 4161-4176
  • Peer Reviewed
• [Journal Article] DDX3 DEAD-boxRNA helicase is required for hepatieis C cirus RNA replication (2007)
  • Author(s): Yasuo Ariumi
  • Journal Title: Journal of Virology 81 Pages: 13922-13926
  • Peer Reviewed
• [Journal Article] Comprehebsive analysis of the effects of ordinaty nuerients on hepatitis Cvirus RNA replication in cell culture (2007)
  • Author(s): Masahiko Yano
  • Journal Title: Antimicrobial Agents and Chemotherapy 51 Pages: 2016-2027
  • Peer Reviewed
• [Presentation] Modulation of dsRNA-induced IFN-beta and inflammatory cytokine production by HCV NS3-4As derived from patients with different hepatic diseases (2008)
  • Author(s): H. Dansako
  • Organizer: 15th International Symposium on Hepatitis C Virus and Related Viruses
  • Place of Presentation: San Antonio, USA
• [Presentation] A new antiviral assay system using living cells harboring genome-length HCV RNA (2008)
  • Author(s): H. Dansako
  • Organizer: 14th International Symposium on Hepatitis C Virus and Related Viruses
  • Place of Presentation: Glasgow, Scotland, UK
• [Presentation] Modulation of dsRNA-induced IFN-beta and inflammatory cytokine productions by HCV NS 3-4 As derived from patients with different hepatic diseases (2008)
  • Author(s): Hiromichi Dansako
  • Organizer: 15^<th> international symposium on hepatitis C virus and related viruses
  • Place of Presentation: San Antonio, Texas, USA
• [Presentation] A new antiviral assay system using the living cells harboring genome-length HCV RNA (2007)
  • Author(s): Hiromichi Dansako
  • Organizer: 14TH International symposium on hepatitis C virus & rekated viruses
  • Place of Presentation: グラスゴー
  • Year and Date: 2007-09-11