The analysis of the host innate immunity induced upon hepatitis virus infection and its inhibitory mechanism by virus protein

• Project/Area Number: 15K19316
• 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: Nitta Sayuri 東京医科歯科大学, 医学部, プロジェクト助教 (20527056)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: ウイルス性肝炎 / 自然免疫 / 肝疾患治療 / 臨床病態解析 / 細胞・組織 / C型肝炎 / B型肝炎 / 自然免疫応答

Outline of Final Research Achievements

In the hepatitis C virus (HCV) study, we demonstrated that the HCV-NS4B protein function to suppress interferon (IFN) activity may related to the effect of IFN therapy to chronic hepatitis C by the analysis using blood samples from patients infected with HCV. In the hepatitis B virus (HBV) study, we demonstrated that RIG-I dependent IFN signal pathway is one of the important innate immune signaling induced during HBV infection. Furthermore, we indicated that interferon stimulated genes induced by IFN is suppressed by HBV. These results above are important and contribute to understand and clarify the mechanisms of the sustained virus infection and the resistance to IFN therapy.

Research Products

• [Journal Article] ITPA gene variation and ribavirin-induced anemia in patients with genotype 2 chronic hepatitis C treated with sofosbuvir plus ribavirin. (2017)
  • Author(s): Murakawa M, Asahina Y, Nagata H, Nakagawa M, Kakinuma S, Nitta S, Kawai-Kitahata F, Otani S, Kaneko S, Miyoshi M, Tsunoda T, Asano Y, Sato A, Itsui Y, Azuma S, Nouchi T, Furumoto Y, Asano T, Chuganji Y, Tohda S, Watanabe M.
  • Journal Title: Hepatol Res Volume: 印刷中 Issue: 11 Pages: 1212-1218
  • DOI: 10.1111/hepr.12867
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hepatic IFNL4 expression is associated with non-response to interferonbased therapy through the regulation of basal interferon-stimulated gene expression in chronic hepatitis C patients. (2017)
  • Author(s): Murakawa M, Asahina Y, Kawai-Kitahata F, Nakagawa M, Nitta S, Otani S, Nagata H, Kaneko S, Asano Y, Tsunoda T, Miyoshi M, Itsui Y, Azuma S, Kakinuma S, Tanaka Y, Iijima S, Tsuchiya K, Izumi N, Tohda S, Watanabe M.
  • Journal Title: J Med Virol Volume: in press Issue: 7 Pages: 1241-1247
  • DOI: 10.1002/jmv.24763
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Bone Morphogenetic Protein-4 Modulates Proliferation and Terminal Differentiation of Fetal Hepatic Stem/Progenitor Cells. (2016)
  • Author(s): Goto F, Kakinuma S, Miyoshi M, Tsunoda T, Kaneko S, Sato A, Asano Y, Otani S, Azuma S, Nagata H, Kawai-Kitahata F, Murakawa M, Nitta S, Itsui Y, Nakagawa M, Asahina Y, Watanabe M.
  • Journal Title: Hepatol Res Volume: 印刷中 Issue: 9 Pages: 941-952
  • DOI: 10.1111/hepr.12823
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Serial measurement of Wisteria floribunda agglutinin positive Mac-2-binding protein is useful for predicting liver fibrosis and the development of hepatocellular carcinoma in chronic hepatitis C patients treated with IFN-based and IFN-free therapy. (2016)
  • Author(s): Nagata H, Nakagawa M, Nishimura-Sakurai Y, Asano Y, Tsunoda T, Miyoshi M, Kaneko S, Goto F, Otani S, Kawai-Kitahata F, Murakawa M, Nitta S, Itsui Y, Azuma S, Kakinuma S, Tojo N, Tohda S, Asahina Y, Watanabe M; Ochanomizu Liver Conference Study Group
  • Journal Title: Hepatol Int. Volume: 10 Pages: 956-964
  • Peer Reviewed
• [Journal Article] Human induced pluripotent stem cell-derived hepatic cell line as a new model for host interaction with hepatitis B virus. (2016)
  • Author(s): Kaneko S, Kakinuma S, Asahina Y, Kamiya A, Miyoshi M, Tsunoda T, Nitta S, Asano Y, Nagata H, Otani S, Kitahata F, Murakawa M, Itsui Y, Nakagawa M, Azuma S, Nakauchi H, Iwamoto M, Watashi K, Wakita T, Sugiyama M, Mizokami M, Shimotohno K, Watanabe M.
  • Journal Title: Sci Rep Volume: ６ Issue: 1 Pages: 29358-29358
  • DOI: 10.1038/srep29358
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Evaluation of IFN resistance in newly established genotype 1b HCV cell culture system. (2016)
  • Author(s): Taniguchi M, Tasaka-Fujita M, Nakagawa M, Watanabe T, Kawai-Kitahata F, Otani S, Goto F, Nagata H, Kaneko S, Nitta S, Murakawa M, Nishimura-Sakurai Y, Azuma S, Itsui Y, Mori K, Yagi S, Kakinuma S, Asahina Y, Watanabe M.
  • Journal Title: J Clin Transl Hepatol Volume: 4 Issue: 1 Pages: 5-11
  • DOI: 10.14218/jcth.2015.00047
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Effects of resistance-associated NS5A mutations in hepatitis C virus on viral production and susceptibility to antiviral reagents. (2016)
  • Author(s): Nitta S, Asahina Y, Matsuda M, Yamada N, Sugiyama R, Masaki T, Suzuki R, Kato N, Watanabe M, Wakita T, Kato T.
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 34652-34652
  • DOI: 10.1038/srep34652
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Matrix metalloproteinase-14 mediates formation of bile ducts and hepatic maturation of fetal hepatic progenitor cells. (2016)
  • Author(s): Otani S, Kakinuma S, Kamiya A, Goto F, Kaneko S, Miyoshi M, Tsunoda T, Asano Y, Kawai-Kitahata F, Nitta S, Nakata T, Okamoto R, Itsui Y, Nakagawa M, Azuma S, Asahina Y, Yamaguchi T, Koshikawa N, Seiki M, Nakauchi H, Watanabe M.
  • Journal Title: Biochem Biophys Res Commun. Volume: 469 Pages: 1062-8
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive analyses of mutations and hepatitis B virus integration in hepatocellular carcinoma with clinicopathological features. (2016)
  • Author(s): Kawai-Kitahata F, Asahina Y, Tanaka S, Kakinuma S, Murakawa M, Sayuri Nitta S, Watanabe T, Otani S, Taniguchi M, Goto F, Nagata H, Kaneko S, Tasaka-Fujita M, Nishimura-Sakurai Y, Azuma S, Itsui Y, Nakagawa M, Tanabe M, Takano S, Fukasawa M, Sakamoto M, Maekawa S, Enomoto N, Watanabe M.
  • Journal Title: Journal of Gastroenterology Volume: 51 Issue: 5 Pages: 473-486
  • DOI: 10.1007/s00535-015-1126-4
  • Peer Reviewed
• [Journal Article] Impaired induction of IL28B and expression of IFNλ4 associated with non-response to interferon-based therapy in chronic hepatitis C. (2015)
  • Author(s): Murakawa M, Asahina Y, Nakagawa M, Sakamoto N, Nitta S, Kusano-Kitazume A, Watanabe T, Kawai-Kitahata F, Otani S, Taniguchi M, Goto F, Nishimura-Sakurai Y, Itsui Y, Azuma S, Kakinuma S, Watanabe M
  • Journal Title: J Gastroenterol Hepatol Volume: 印刷中 Issue: 6 Pages: 1075-84
  • DOI: 10.1111/jgh.12902
  • Peer Reviewed / Open Access
• [Presentation] HCV NS5A阻害剤耐性変異株の特徴と薬剤感受性に関する検討 (2016)
  • Author(s): 新田沙由梨、朝比奈靖浩、加藤孝宣
  • Organizer: 第102回日本消化器病学会総会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2016-04-21
• [Presentation] In Vitro Characterization and Drug Sensitivity Analysis for HCV NS5A Resistance-Associated Variants (2016)
  • Author(s): Sayuri Nitta, Yasuhiro Asahina, Takaji Wakita, Takanobu Kato
  • Organizer: APASL2016
  • Place of Presentation: グランドプリンスホテル新高輪（東京都港区）
  • Year and Date: 2016-02-21
  • Int'l Joint Research
• [Presentation] C型慢性肝炎治療における薬剤耐性変異ウイルスに関する課題と対策 (2016)
  • Author(s): 新田沙由梨、加藤孝宣、朝比奈靖浩
  • Organizer: 日本肝臓学会東部会
  • Place of Presentation: 京王プラザホテル新宿、東京
• [Presentation] NS5A阻害剤耐性変異のHCVライフサイクルへの影響と薬剤感受性の解析 (2016)
  • Author(s): 新田沙由梨、朝比奈靖浩、加藤孝宣
  • Organizer: 日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ幕張、千葉
• [Presentation] Daclatasvir(DCV)耐性変異がC型肝炎ウイルス(HCV)の増殖と薬剤感受性に与える影響 (2016)
  • Author(s): 新田沙由梨、朝比奈靖浩、加藤孝宣
  • Organizer: 日本消化器病学会総会
  • Place of Presentation: 京王プラザホテル新宿、東京
• [Presentation] Effects of Resistance Mutations of NS5A Inhibitor on Viral Production and Susceptibility to Anti-HCV Reagents in Recombinant Hepatitis C Viruses with NS5A of Genotype 1b (2015)
  • Author(s): Sayuri Nitta, Yasuhiro Asahina, Takaji Wakita, Takanobu Kato
  • Organizer: AASLD the Liver Meeting 2015
  • Place of Presentation: San Fransisco（USA）
  • Year and Date: 2015-11-15
  • Int'l Joint Research
• [Presentation] HCV感染培養系を用いたDaclatasvir耐性変異株の抗HCV薬に対する薬剤感受性の評価 (2015)
  • Author(s): 新田沙由梨、村山麻子、藤田めぐみ、山田典栄、政木隆博、脇田隆字、朝比奈靖浩、加藤孝宣
  • Organizer: 第51回日本肝臓学会総会
  • Place of Presentation: ホテル日航熊本（熊本県熊本市）
  • Year and Date: 2015-05-21
• [Book] 新ウイルス性肝炎学 (2015)
  • Author(s): 新田沙由梨、坂本直哉、朝比奈靖浩
  • Total Pages: 704
  • Publisher: 日本臨床