Machinery for hepatitis B virus entry regulated by host protein kinase

• Project/Area Number: 19K16672
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49060:Virology-related
• Research Institution: Kyushu University
• Principal Investigator: Masashi Iwamoto 九州大学, 理学研究院, 特別研究員 (40825882)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: HBV / プロテインキナーゼ / EGFR / HDV / entry / キナーゼ / infection

Outline of Research at the Start

B型肝炎ウイルス(HBV)感染には受容体であるNTCPが必要である。一方でNTCP発現だけでHBV 感染が成立するわけではなく、ウイルスと受容体吸着後の侵入過程での感染成立決定機序は明らかとなっていない。申請者は、宿主のプロテインキナーゼ活性化 により細胞のHBV感染感受性が上昇する予備的結果を得ている。本研究ではこれまでの検討結果を踏まえて、HBV侵入過程のうちウイルス”内在化”を制御する宿主因子とその制御機序を明らかにする。また、内在化過程を制御する宿主因子を標的とした阻害剤の抗ウイルス活性を評価することで、基礎的知見から応用を見据えた研究を行う。

Outline of Final Research Achievements

Machinery for entry of hepatitis B virus (HBV) into the host cells have been largely unknown. Here, we reported epidermal growth factor receptor (EGFR) as essential host factor for HBV entry after attachment to sodium taurocholate co-transporting polypeptide (NTCP), known as HBV host receptor, on the plasma membrane. EGFR triggered HBV internalization thought binding to NTCP. Future studies revealed that role of EGFR on HBV entry was not only inducing viral internalization, but also regulating the trafficking of HBV to late endosome for functional infection. These results are useful for understanding the mechanism of HBV infection as well as establishment of novel anti-HBV agents.

Academic Significance and Societal Importance of the Research Achievements

本研究課題により、長年明らかでなかったHBVの細胞内侵入機構の一端を明らかにした。EGFRはHBV感染に必須な宿主因子であり、その感染制御機構を同定した。EGFRはこれまでに抗がん剤の標的として着目されてきたことにより、多くの阻害剤が報告されており、これらのうち少なくともゲフィチニブはEGFRの機能を阻害することでHBV感染を減少させることを細胞培養レベルで明らかにした。本研究で得た知見はHBV感染分子機構の理解を推し進めたのみならず、新しいHBV感染治療戦略を提案するもので、 EGFRが新規HBV治療薬の標的となり得る可能性を示唆した。

Research Products

• [Journal Article] Identification of novel avian and mammalian deltaviruses provides new insights into deltavirus evolution (2021)
  • Author(s): Iwamoto Masashi、Shibata Yukino、Kawasaki Junna、Kojima Shohei、Li Yung-Tsung、Iwami Shingo、Muramatsu Masamichi、Wu Hui-Lin、Wada Kazuhiro、Tomonaga Keizo、Watashi Koichi、Horie Masayuki
  • Journal Title: Virus Evolution Volume: 7 Issue: 1
  • DOI: 10.1093/ve/veab003
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The machinery for endocytosis of epidermal growth factor receptor coordinates the transport of incoming hepatitis B virus to the endosomal network. (2020)
  • Author(s): Iwamoto M, Saso W, Nishioka K, Ohashi H, Sugiyama R, Ryo A, Ohki M, Yun JH, Park SY, Ohshima T, Suzuki R, Aizaki H, Muramatsu M, Matano T, Iwami S, Sureau C, Wakita T, Watashi K
  • Journal Title: J Biol Chem Volume: 295 Issue: 3 Pages: 800-807
  • DOI: 10.1074/jbc.ac119.010366
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Anti‐viral effects of interferon‐λ3 on hepatitis B virus infection in cell culture (2020)
  • Author(s): Yamada Norie、Murayama Asako、Shiina Masaaki、Aly Hussein Hassan、Iwamoto Masashi、Tsukuda Senko、Watashi Koichi、Tanaka Tomohisa、Moriishi Kohji、Nishitsuji Hironori、Sugiyama Masaya、Mizokami Masashi、Shimotohno Kunitada、Muramatsu Masamichi、Murata Kazumoto、Kato Takanobu
  • Journal Title: Hepatology Research Volume: 50 Issue: 3 Pages: 283-291
  • DOI: 10.1111/hepr.13449
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Epidermal growth factor receptor is a host entry cofactor triggering hepatitis B virus internalization (2019)
  • Author(s): M. Iwamoto, W. Saso, R. Sugiyama, K. Ishii, M. Ohki, S. Nagamori, R. Suzuki, H. Aizaki, A. Ryo, J-H Yun, S-Y Park, N. Ohtani, M. Muramatsu, S. Iwami, Y. Tanaka, C. Sureau, T. Wakita and K. Watashi
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 116 Issue: 17 Pages: 8487-8492
  • DOI: 10.1073/pnas.1811064116
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Synthesis of nucleotide analogues, EFdA, EdA and EdAP, and the effect of EdAP on hepatitis B virus replication (2019)
  • Author(s): Kamata Mai、Takeuchi Toshifumi、Hayashi Ei、Nishioka Kazane、Oshima Mizuki、Iwamoto Masashi、Nishiuchi Kota、Kamo Shogo、Tomoshige Shusuke、Watashi Koichi、Kamisuki Shinji、Ohrui Hiroshi、Sugawara Fumio、Kuramochi Kouji
  • Journal Title: Bioscience, Biotechnology, and Biochemistry Volume: 84 Issue: 2 Pages: 217-227
  • DOI: 10.1080/09168451.2019.1673696
  • Peer Reviewed
• [Presentation] Epidermal growth factor receptor as a novel host entry cofactor that triggers hepatitis B virus internalization. (2019)
  • Author(s): Masashi Iwamoto, Wakana Saso, Mio Ohki, Ryosuke Suzuki, Hideki Aizaki, Akihide Ryo, Sam-Yong Park, Masamichi Muramatsu, Shingo Iwami, Yasuhito Tanaka, Camille Sureau, Takaji Wakita, Koichi Watashi
  • Organizer: 2019 International Meeting on Molecular Biology of Hepatitis B Viruses
  • Int'l Joint Research
• [Book] Elucidation of hepatitis B virus invasion control mechanism by host protein kinase (2021)
  • Author(s): Masashi Iwamoto
  • Total Pages: 3
  • Publisher: Science Impact Ltd