肝炎ウイルスの排除・持続感染化に関わる宿主因子の動物種及び臓器特異性の解明

• Project Area: Molecular basis of host cell competency in virus infection
• Project/Area Number: 15H01272
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: 小原 道法 公益財団法人東京都医学総合研究所, ゲノム医科学研究分野, プロジェクトリーダー (10250218)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥10,400,000 (Direct Cost: ¥8,000,000、Indirect Cost: ¥2,400,000); Fiscal Year 2016: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
• Keywords: ウイルス / 感染症 / 微生物 / 免疫学

Outline of Annual Research Achievements

C型肝炎ウイルス(HCV)感染者に対する特異的免疫賦活化による根治を目指した治療的ワクチンの開発を目的とする。HCVは感染することにより80％の被感染者が慢性化してしまうが、20％は慢性化せず自己の免疫によりウイルスを排除する。これらのことは、免疫を賦活化することによりウイルスのコントロールができる可能性を示唆している。HCV感染に対する免疫反応は感染防御のみならず、感染者における病態ときわめて密接に関連している。このためにHCV特異的免疫反応を解析し、HCV肝炎の肝硬変、肝癌への進展を阻害し解除する方策を立てることは極めて重要である。本研究ではHCVによる宿主免疫抑制・回避機序を明らかにし、特異的免疫賦活化による根治を目指した治療的ワクチンの可能性を探索する事を目的とする。DNA ワクチンや組換えワクシニアウイルスワクチンの単独投与以上にprime-boostワクチン投与でHCV特異的細胞性免疫の増強が認められ、肝臓中のコアタンパクも有意に減少し、肝数値の改善も認められた。さらに、prime-boost ワクチンの組み合わせは、homologousなものよりもN25 DNAとrVV CN2もしくはCN2 DNA とrVV N25の組み合わせのようなheterologous prime-boostの場合の方が細胞性免疫の誘導能が高かった。これまで細胞性免疫の誘導が困難であったHCV全タンパク質コードTgマウスにおいてもHeterologous prime-boost ワクチンが有効であることが示唆された。Heterologous prime-boostによる免疫不応等からの再活性化機序について検討を進めている。

Research Progress Status

28年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

28年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Susceptibility and initial immune response of Tupaia belangeri cells to dengue virus infection (2017)
  • Author(s): Kayesh MEH, Kitab B, Sanada T, Hayasaka D, Morita K, Kohara M, *Tsukiyama-Kohara K.
  • Journal Title: Infect Genet Evol. Volume: 51 Pages: 203-210
  • DOI: 10.1016/j.meegid.2017.04.003
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Selective inhibitor of Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse model (2017)
  • Author(s): Yuko Tokunaga, Yosuke Osawa, Takahiro Ohtsuki, Yukiko Hayashi, Kenzaburo Yamaji, Daisuke Yamane, Mitsuko Hara, Keisuke Munekata, Kyoko Tsukiyama-Kohara, Tsunekazu Hishima, Soichi Kojima, Kiminori Kimura, and *Michinori Kohara
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 325-325
  • DOI: 10.1038/s41598-017-00282-w
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Transmission of HBV-DNA mediated by ceramide-triggered extracellular vesicles (2016)
  • Author(s): Takahiro Sanada, Yuichi Hirata, Yutaka Naito, Naoki Yamamoto, Yoshiaki Kikkawa, Yuji Ishida, Chihiro Yamasaki, Chise Tateno, Takahiro Ochiya, and *Michinori Kohara
  • Journal Title: Cellular and Molecular Gastroenterology and Hepatology Volume: 3 Issue: 2 Pages: 272-283
  • DOI: 10.1016/j.jcmgh.2016.10.003
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Immature Core protein of hepatitis C virus induces an unfolded protein response through inhibition of ERAD-L in a yeast model system (2016)
  • Author(s): Takahashi S, Sato N, Kikuchi J, Kakinuma H, Okawa J, Masuyama Y, Iwasa S, Irokawa H, Hwang GW, Naganuma A, Kohara M, *Kuge S.
  • Journal Title: Genes Cells Volume: 22 Issue: 2 Pages: 160-173
  • DOI: 10.1111/gtc.12464
  • Peer Reviewed
• [Journal Article] Sensitization with vaccinia virus harboring hemagglutinin recovers the immune potential against highly pathogenic H5N1 influenza virus in non-human primates (2016)
  • Author(s): Fumihiko Yasui, Yasushi Itoh, Ai Ikejiri, Masahiro Kitabatake, Nobuo Sakaguchi, Keisuke Munekata, Shintaro Shichinohe, Yukiko Hayashi, Hirohito Ishigaki, Misako Nakayama, Yoshihiro Sakoda, Hiroshi Kida, Kazumasa Ogasawara, *Michinori Kohara
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 37915-37915
  • DOI: 10.1038/srep37915
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Extracellular Vesicles Including Exosomes Regulate Innate Immune Responses to Hepatitis B Virus Infection. (2016)
  • Author(s): Takahisa Kouwaki, Yoshimi Fukushima, Takuji Daito, Takahiro Sanada, Naoki Yamamoto, Edin J. Mifsud, Chean Ring Leong, Kyoko Tsukiyama-Kohara, Michinori Kohara, Misako Matsumoto, Tsukasa Seya and *Hiroyuki Oshiumi
  • Journal Title: Frontiers in Immunology. Volume: 7 Pages: 335-335
  • DOI: 10.3389/fimmu.2016.00335
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Novel pH-sensitive multifunctional envelope-type nanodevice for siRNA-based treatments for chronic HBV infection (2016)
  • Author(s): Yamamoto, N. Sato, Y. Munakata, T. Kakuni, M. Tateno, C. Sanada, T. Hirata, Y. Murakami, S. Tanaka, Y. Chayama, K. Hatakeyama, H. Hyodo, M. Harashima, H. Kohara, M.
  • Journal Title: Journal of hepatology Volume: 64 Issue: 3 Pages: 547-455
  • DOI: 10.1016/j.jhep.2015.10.014
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Property of hepatitis B virus replication in Tupaia belangeri hepatocytes (2016)
  • Author(s): Takahiro Sanada, Kyoko Tsukiyama-Kohara, Naoki Yamamoto, Sayeh Ezzikouri, Soumaya Benjelloun, Shuko Murakami, Yasuhito Tanaka, Chise Tateno, and Michinori Kohara
  • Journal Title: Biochem Biophys Res Commun Volume: 469 Issue: 2 Pages: 229-235
  • DOI: 10.1016/j.bbrc.2015.11.121
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hepatitis C virus attenuates mitochondrial lipid β-oxidation by downregulating mitochondrial trifunctional-protein expression. (2015)
  • Author(s): Amako Y, Munakata T, Kohara M, Siddiqui A, Peers C, Harris M.
  • Journal Title: J Virol Volume: 89 Issue: 8 Pages: 4092-4101
  • DOI: 10.1128/jvi.01653-14
  • Peer Reviewed / Open Access
• [Journal Article] Generation of Novel Chimeric Mice with Humanized Livers by Using Hemizygous cDNA-uPA/SCID Mice (2015)
  • Author(s): Chise Tateno, Yosuke Kawase, Yoshimi Tobita, Satoko Hamamura, Hiroki Ohshita, Hiroshi Yokomichi, Harumi Sanada, Masakazu Kakuni, Akira Shiota, Yuha Kojima1, Yuji Ishida, Hiroshi Shitara, Naoko A. Wada, Hiromi Tateishi, Masayuki Sudoh, Shin-Iichiro Nagatsuka, Kou-ichi Jishage, Michinori Kohara
  • Journal Title: PLoS One. Volume: 10 Issue: 11 Pages: e0142145-e0142145
  • DOI: 10.1371/journal.pone.0142145
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] M2 macrophages play critical roles in progression of inflammatory liver disease in hepatitis C virus transgenic mice. (2015)
  • Author(s): 1.Ohtsuki T, Kimura K, Tokunaga Y, Tsukiyama-Kohara K, Tateno C, Hayashi Y, Hishima T, Kohara M
  • Journal Title: J Virol Volume: Oct 14;90(1) Issue: 1 Pages: 300-7
  • DOI: 10.1128/jvi.02293-15
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] C型肝炎ウイルス感染による脂肪滴蓄積へのPLA2G4Cの関与 (2016)
  • Author(s): M. Ito, M. Fukasawa, M. Kohara, T. Suzuki
  • Organizer: 第64回日本ウイルス学会学術集会
  • Place of Presentation: 札幌コンベンションセンター（札幌）
  • Year and Date: 2016-10-23
• [Presentation] Amelioration of HCV liver fibrosis by selective inhibitor of Wnt/β-catenin/CBP signaling (2016)
  • Author(s): Tokunaga Y., Osawa Y., Ohtsuki K., Yamaji K., Yamane D., Munekata K., Hara M., Kojima S., Kimura K., Kohara M
  • Organizer: 23rd International Symposium on Hepatitis C Virus and Related Viruses
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2016-10-11
  • Int'l Joint Research
• [Presentation] Roles of Iron and fatty acid desaturase in the restriction of lipid peroxidation-sensitive hepatitis C viruses (2016)
  • Author(s): Yamane D., Lemon S.M., Kohara M.
  • Organizer: 第15回あわじしま感染症・免疫フォーラム
  • Place of Presentation: 淡路夢舞台国際会議場 （兵庫県淡路市）
  • Year and Date: 2016-09-06
• [Presentation] Pathogenesis and Immuno-therapy of Hepatitis C virus Infection (2016)
  • Author(s): Tsukiyama-Kohara K., Sekiguchi S., Kimura K., Ohtsuki T., Tokunaga Y., Kohara M.
  • Organizer: 10th Vaccine Congress
  • Place of Presentation: Amsterdam, the Netherlands
  • Year and Date: 2016-09-04
  • Int'l Joint Research
• [Presentation] Transmission of HBV-DNA mediated by extracellular vesicles. Keystone Symposia Exosomes/Microvesicles (2016)
  • Author(s): Sanada T., Hirata Y., Naito Y.,Yamamoto N., Ishida Y., Yamasaki C., Tateno C., Ochiya T., Kohara M.
  • Organizer: Novel Mechanisms of Cell-Cell Communication
  • Place of Presentation: Keystone Resort, Colorado (USA)
  • Year and Date: 2016-06-19
  • Int'l Joint Research
• [Presentation] Heterologous vaccination with DNA vaccine and recombinant vaccinia virus carrying the cDNA of HCV induced effective immunity in mouse model (2015)
  • Author(s): Yumiko Shiomaga, Michinori Kohara, Yasuhiro Yasutomi
  • Organizer: 第63回日本ウイルス学会学術集会
  • Place of Presentation: 福岡国際会議場（福岡県・福岡市）
  • Year and Date: 2015-11-22
  • Int'l Joint Research
• [Presentation] M2 macrophages play critical roles in progression of inflammatory liver disease in hepatitis C virus (2015)
  • Author(s): Takahiro Ohtsuki, Kiminori Kimura, Yuko Tokunaga, Kyoko Tsukiyama-Kohara, Michinori Kohara
  • Organizer: 22nd International Symposium on Hepatitis C virus and Related viruses
  • Place of Presentation: Strasbourg (France)
  • Year and Date: 2015-10-09
  • Int'l Joint Research
• [Presentation] Exosomes contain HBV DNA and HBs Ag (2015)
  • Author(s): Takahiro Sanada, Yuichi Hirata, Yutaka Naito, Naoki Yamamoto, Yuji Ishida, Chihiro Yamasaki, Chise Tateno, Takahiro Ochiya, Michinori Kohara
  • Organizer: 2015International Meeting on Molecular Biology of Hepatitis B Viruses
  • Place of Presentation: Dolce Bad Nauheim (Germany)
  • Year and Date: 2015-10-04
  • Int'l Joint Research
• [Presentation] siRNA-based therapies to chronic HBV infection using a novel pH-sensitive multifunctional envelope-type nanodevice (2015)
  • Author(s): Naoki Yamamoto, Yusuke Sato, Tsubasa Munakata, Takahiro Sanada, Masakazu Kakuni, Chise Tateno, Shuko Murakami, Yasuhito Tanaka, Kazuaki Chayama, Hideyoshi Harashima, Michinori Kohara
  • Organizer: 2015International Meeting on Molecular Biology of Hepatitis B Viruses
  • Place of Presentation: Dolce Bad Nauheim (Germany)
  • Year and Date: 2015-10-04
  • Int'l Joint Research
• [Presentation] Selective inhibitor of Wnt/β-catenin/CBP signaling ameliotates hepatitis C virus-induced liver fibrosis in mice (2015)
  • Author(s): Yuko Tokunaga, Kiminori Kimura, Takahiro Ohtuki, Yukiko Hayashi, Keisuke Munekata, Tsunekazu Hishima, Michinori Kohara
  • Organizer: 50th The International Liver Congress (EASL)
  • Place of Presentation: Vienna (Austria)
  • Year and Date: 2015-04-22
  • Int'l Joint Research
• [Book] 別冊BIO Clinica 慢性炎症とがん (2015)
  • Author(s): 小原道法、小原恭子
  • Total Pages: 5
  • Publisher: 北隆館
• [Remarks] 東京都医学総合研究所
  • URL: http://www.igakuken.or.jp