Comprehensive analysis on genes and molecular pathways in host cells associated with Hepatitis C virus infection using next-generation sequencing technology

• Project/Area Number: 23790778
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: SAKURAI Yuki 東京医科歯科大学, 医学部附属病院, 医員 (70547455)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: C型肝炎ウイルス / 包括的解析 / pathway解析 / 宿主・ウイルス相互作用 / 自然免疫

Research Abstract

The objective of this research project is to clarify the molecular pathways in host cells related to life cycle of Hepatitis C virus (HCV) infection, including entry and replication of HCV. Comprehensive microarray analysis and hierarchical clustering of gene expression data revealed that the expressions of genes related to molecular pathways of lipid metabolism are significantly increased in host cells expressing HCV replicon. Furthermore, analysis on the interaction between HCV-NS4B protein and cellular interferon (IFN)-mediated antiviral signaling clarified that NS4B specifically binds STING, and that NS4B suppresses STING-mediated IFN production. These results showed that we explored the new interaction between HCV and host signal protein related to HCV replication. Disruption of that interaction could constitute a novel therapeutic strategy forthe eradication of HCV.

Research Products

• [Journal Article] Hepatitis C virus NS4B protein targets STING and abrogates RIG-I-mediated type-I interferon-dependent innate immunity (2013)
  • Author(s): Nitta S, Sakamoto N, Nakagawa M, Kakinuma S, Mishima K, Kusano-kitazume A, Kiyohashi K, Murakawa M, Nishimura-Sakurai Y, Azuma S, Tasaka-Fujita M, asahina Y, Yoneyama M, Fujita T, Watanabe M
  • Journal Title: Hepatology Volume: 57 Issue: 1 Pages: 46-58
  • DOI: 10.1002/hep.26017
  • Peer Reviewed
• [Journal Article] Association of ITPA gene variant and serum ribavirin concentration with blood cells decline in pegylated interferon-alfa plus ribavirin therapy for chronic hepatitis C. (2013)
  • Author(s): Nakagawa M, Sakamoto N, Watanabe T, Nishimura-Sakurai Y, Onozuka I, Azuma S, Kakinuma S, Nitta S, Kiyohashi K,Kusano-Kitazume A, Murakawa M, Yoshino K, Itsui Y, Tanaka Y, Mizokami M,Watanabe M, Ochanomizu Liver Conference Study Group
  • Journal Title: Hepatol Int Volume: 7(1) Issue: 1 Pages: 153-161
  • DOI: 10.1007/s12072-012-9363-6
  • Peer Reviewed
• [Journal Article] 多血性肝細胞癌の検出能に関するGd-EOB-DTPA造影MRIとCTAP/CTHAとの比較検討 (2013)
  • Author(s): 東正新,朝比奈靖浩,櫻井幸,吉野耕平,幾世橋佳,新田沙由梨,北詰晶子,村川美也子,中川美奈,柿沼晴,渡辺守
  • Journal Title: 医学と薬学 Volume: 69巻1号 Pages: 64-66
• [Journal Article] 多血性肝細胞癌の検出能に関するGd-EOB-DTPA造影MRIとCTAP/CTHAとの比較検討 (2013)
  • Author(s): 東 正新、櫻井 幸、他
  • Journal Title: 医学と薬学 Volume: 69 Pages: 64-66
• [Journal Article] Association of ITPA gene variant and serum ribavirin concentration with blood cells decline in pegylated interferon-alfa plus ribavirin therapy for chronic hepatitis C (2013)
  • Author(s): Nakagawa M, Nishimura-Sakurai Y, et al.
  • Journal Title: Hepatol Int Volume: in press
  • Peer Reviewed
• [Journal Article] Identification of novel N-(morpholine-4-carbonyloxy) amidine compounds as potent inhibitors against hepatitis C virus replication (2012)
  • Author(s): Kusano-Kitazume A, Sakamoto N, Okuno Y, Sekine-Osajima Y, Nakagawa M, Kakinuma S, Kiyonashi K, Nitta S, Murakawa M, Azuma S, Nishimura-Sakurai Y, Hagiwara M, Watanabe M
  • Journal Title: Antimicrob Agent Chemother Volume: 56(3) Issue: 3 Pages: 1315-23
  • DOI: 10.1128/aac.05764-11
  • Peer Reviewed / Open Access
• [Journal Article] The Japan Non-B, Non-C Liver Cirrhosis Study Group. Survey of non-B, non-C liver cirrhosis in Japan. (2012)
  • Author(s): Suzuki Y
  • Journal Title: Hepatol Res. Volume: - Issue: 10 Pages: 1020-1031
  • DOI: 10.1111/hepr.12056
  • Peer Reviewed
• [Journal Article] HCV-NS4B蛋白とIFN発現系シグナル分子との分子間相互作用の解析 (2012)
  • Author(s): 新田沙由梨,坂本直哉,藤田めぐみ,柿沼晴,村川美也子,北詰晶子,幾世橋佳,船岡祐介,渡辺貴子,植山真由美,小野塚泉,櫻井幸,中川美奈,東正新,渡辺守
  • Journal Title: 消化器と免疫 Volume: 48号 Pages: 174-177
• [Journal Article] HCV-NS4B蛋白とIFN発現系シグナル分子との分子間相互作用の解析 (2012)
  • Author(s): 新田 沙由梨、櫻井 幸、他
  • Journal Title: 消化器と免疫 Volume: 48 Pages: 174-177
• [Journal Article] Serum interleukin-6 levels correlate with resistance to treatment of chronic hepatitis C infection withpegylated-interferon-α2b plus ribavirin (2011)
  • Author(s): Ueyama M, Nakagawa M, Sakamoto N,Onozuka I, Funaoka Y, Watanabe T, Nitta S, Kiyohashi K, Kitazume A, Murakawa M, Nishimura-Sakurai Y, Sekine-Osajima Y, Itsui Y, Azuma S, Kakinuma S, Watanabe M and the Ochanomizu-Liver Conference Study Group
  • Journal Title: Antivir Ther Volume: 16 Issue: 7 Pages: 1081-1091
  • DOI: 10.3851/imp1864
  • Peer Reviewed
• [Journal Article] Studies on virus kinetics using infectious fluorescence-tagged hepatitis C virus cell culture (2011)
  • Author(s): Yamamoto M, Sakamoto N, Nakamura T, Itsui Y, Nakagawa M, Nishimura-Sakurai Y, Kakinuma S, Azuma S, Kato T, Wakita T, Watanabe M
  • Journal Title: Hepatol Res Volume: 41 Issue: 3 Pages: 258-269
  • DOI: 10.1111/j.1872-034x.2010.00771.x
  • Peer Reviewed
• [Journal Article] Association of IL28B variants with response to pegylated-interferon alpha plus ribavirin combination therapy reveals intersubgenotypic differences between genotypes 2a and 2b (2011)
  • Author(s): Sakamoto N, Nakagawa M, Azuma S, Watanabe M, et al.
  • Journal Title: J Med Virol Volume: 83 Issue: 5 Pages: 871-878
  • DOI: 10.1002/jmv.22038
  • Peer Reviewed
• [Journal Article] Inhibitory effect of a triterpenoid compound, with or without alpha interferon, on hepatitis C virus infection (2011)
  • Author(s): Watanabe T, Sakamoto N, Nakagawa M, Azuma S, Watanabe M, et al.
  • Journal Title: Antimicrob Agents Chemother Volume: 55(6) Issue: 6 Pages: 2537-2545
  • DOI: 10.1128/aac.01780-10
  • Peer Reviewed
• [Journal Article] Serum interleukin-6 levels correlate with resistance to treatment of chronic hepatitis C infection with pegylated-interferon-α2b plus ribavirin. (2011)
  • Author(s): Ueyama M, Nishimura-Sakurai Y, et al.
  • Journal Title: Antivir Ther Volume: 16 Issue: 7 Pages: 1081-91
  • DOI: 10.3851/imp1933
  • Peer Reviewed
• [Presentation] Antiviral effetcts and action mechanisms of novel N-(morpholine-4-carbonyloxy) amidine compounds against hepatitis C virus (2012)
  • Author(s): Kusano-Kitazume A, Sakamoto N, Okuno Y, Mori, K, Nakagawa, M, Kakinuma S, Nitta S, Murakawa M, Azuma S, Nishimura-Sakurai Y, Matsumoto A, Hagiwara M, Asahina Y, Watanabe M
  • Organizer: 63rd Annual Meeting of American Association for the Study of Liver Diseases
  • Place of Presentation: Boston, MA.
  • Year and Date: 2012-11-11
• [Presentation] Impaired IL28B gene induction and poor IL28B promoter activity influenced by the IL28B minor allele are closely associated with a null response to interferon in chronic hepatitis C patients (2012)
  • Author(s): Asahina Y, Murakawa M, Sakamoto N,Kakinuma S, Nakagawa M, Azuma S, Nishimura-Sakurai Y, Nitta S,Kusano-Kitazume A, Watanabe M
  • Organizer: 63rd Annual Meetingof American Association for the Study ofLiver Diseases
  • Place of Presentation: Boston, MA.
  • Year and Date: 2012-11-11
• [Presentation] 抗HCV活性を有するN-(morpholine-4-carbonyloxy)amidine化合物の同定 (2012)
  • Author(s): 北詰晶子,坂本直哉,奥野友紀子,中川美奈,柿沼晴,幾世橋佳,新田沙由梨,村川美也子,東正新,櫻井幸,萩原正敏,渡辺守
  • Organizer: JDDW2012第16回日本肝臓学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2012-10-10
• [Presentation] Impaired induction of IL28B expression in PBMC is associatedwith null response to interferon therapy in chronic hepatitis C (2012)
  • Author(s): Murakawa M, Sakamoto N, Nakagawa M, Kawai F, Fuziki J, Otani S, Yamanaka H, Kitazume A, Nitta S, Watanabe T,Sakurai Y, Kakinuma S, Asahina Y, Watanabe M
  • Organizer: 19th International Symposium on Hepatitis C Virus and Related Viruses.
  • Place of Presentation: Venice,Italy
  • Year and Date: 2012-10-08
• [Presentation] インターフェロンλ産生能および抗ウイルス治療効果に関わるIL28B遺伝子多型(SNP)の機能解析 (2012)
  • Author(s): 村川美也子,坂本直哉,中川美奈,吉野耕平,幾世橋佳,北詰晶子,新田沙由梨,渡辺貴子,櫻井幸,東正新,柿沼晴,渡辺守
  • Organizer: 第48回日本肝臓学会総会
  • Place of Presentation: 金沢
  • Year and Date: 2012-06-08
• [Presentation] 非B非C肝硬変の肝発癌に関連する因子の検討 (2012)
  • Author(s): 櫻井幸,中川美奈,東正新,柿沼晴,坂本直哉,渡辺守
  • Organizer: 第48回日本肝臓学会総会
  • Place of Presentation: 金沢
  • Year and Date: 2012-06-07
• [Presentation] EOB-MRIおよびAngio-CTによる多血性肝細胞癌に関する検討 (2012)
  • Author(s): 東正新,坂本直哉,櫻井幸,吉野耕平,幾世橋佳,新田沙由梨,北詰晶子,村川美也子,中川美奈,柿沼晴,渡辺守
  • Organizer: 第48回日本肝臓学会総会
  • Place of Presentation: 金沢
  • Year and Date: 2012-06-07
• [Presentation] 肝細胞癌におけるEOB-DTPA造影MRIとAngio-CTの比較検討 (2012)
  • Author(s): 東正新,坂本直哉,櫻井幸,吉野耕平,幾世橋佳,新田沙由梨,北詰晶子,村川美也子,中川美奈,柿沼晴,渡辺守
  • Organizer: 第98回日本消化器病学会総会
  • Place of Presentation: 東京
  • Year and Date: 2012-04-19
• [Presentation] Treatment and outcomes for elderly patients with hepatocellular caricinoma (2012)
  • Author(s): Azuma S, Sakamoto N, Sakurai Y, Nakagawa M, Kakinuma S, Watanabe M
  • Organizer: The 22nd Conference of the Asian PacificAssociation for the Study of the Liver
  • Place of Presentation: Taipei, Taiwan
  • Year and Date: 2012-02-18
• [Presentation] ITPA gene variant protects against treatment-induced anemia and improves viral clearance by pegylated interferon-alfa and ribavirin therapy in chronic hepatitis C patients (2011)
  • Author(s): Sakamoto N, Tanaka Y, Nakagawa M, Yatsuhashi H, Nishiguchi S, Enomoto N, Azuma S, Nishimura-Sakurai Y, Kakinuma S, Nishida N, Tokunaga K, Mizokami M, Watanabe M
  • Organizer: 62nd Annual Meeting of American Association for the Study of Liver Diseases
  • Place of Presentation: San Francisco, CA.
  • Year and Date: 2011-11-04
• [Presentation] 非B非C肝硬変の実態に関する検討 (2011)
  • Author(s): 櫻井幸,中川美奈,坂本直哉
  • Organizer: 第15回日本肝臓学会大会
  • Place of Presentation: 福岡.
  • Year and Date: 2011-10-20
• [Presentation] 高齢者肝細胞癌患者に対する治療方法とその成績 (2011)
  • Author(s): 東正新,坂本直哉,櫻井幸,吉野耕平,幾世橋佳,新田沙由梨,北詰晶子,村川美也子,中川美奈,柿沼晴,渡辺守
  • Organizer: 第15回日本肝臓学会大会
  • Place of Presentation: 福岡.
  • Year and Date: 2011-10-20
• [Presentation] C型慢性肝炎のPEG-IFNα-2b/Ribavirin併用療法におけるITPA遺伝子の臨床的意義 (2011)
  • Author(s): 櫻井幸,中川美奈,坂本直哉,植山真由美,筬島裕子,東正新,柿沼晴,田中靖人,溝上雅史,渡辺守
  • Organizer: 第47回日本肝臓学会総会
  • Place of Presentation: 東京.
  • Year and Date: 2011-06-03
• [Presentation] 非B非C肝硬変の実態に関する検討 (2011)
  • Author(s): 櫻井 幸、中川美奈、坂本直哉
  • Organizer: 第15回日本肝臓学会大会
  • Place of Presentation: 福岡
• [Presentation] C型慢性肝炎のPEG-IFNα-2b/Ribavirin併用療法におけるITPA遺伝子の臨床的意義 (2011)
  • Author(s): 櫻井 幸、他
  • Organizer: 第47回日本肝臓学会総会
  • Place of Presentation: 東京
• [Presentation] 非B非C肝硬変の肝発癌に関連する因子の検討
  • Author(s): 櫻井 幸、他
  • Organizer: 第48回日本肝臓学会総会
  • Place of Presentation: 金沢
• [Presentation] Impaired IL28B gene induction and poor IL28B promoter activity influenced by the IL28B minor allele are closely associated with a null response to interferon in chronic hepatitis C patients
  • Author(s): Asahina Y, Nishimura-Sakurai Y, et al.
  • Organizer: 63rd Annual Meeting of American Association for the Study of Liver Diseases
  • Place of Presentation: Boston
• [Presentation] Antiviral effetcts and action mechanisms of novel N-(morpholine-4-carbonyloxy) amidine compounds against hepatitis C virus
  • Author(s): Kusano-Kitazume A, Nishimura-Sakurai Y, et al.
  • Organizer: 63rd Annual Meeting of American Association for the Study of Liver Diseases
  • Place of Presentation: Boston