Mechanistic analysis of persistent infection of HCV in non-hepatic cells

• Project/Area Number: 18K07146
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49060:Virology-related
• Research Institution: Osaka University
• Principal Investigator: Ono Chikako 大阪大学, 微生物病研究所, 助教 (30626437)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: C型肝炎ウイルス / miRNA / 肝外病変 / HCV / マイクロRNA / 感染症

Outline of Final Research Achievements

The main target organ for hepatitis C virus (HCV) is the liver, but it has been clinically reported to cause lesions in tissues other than the liver. In this study, we showed that liver-specific microRNAs other than miR-122 can contribute to the enhancement of HCV-RNA replication in the process of persistent HCV infection in non-liver cells. In addition, the various miRNAs obtained in this study interact with the 5'UTR of HCV-RNA to enhance the stability of not only the secondary structure but also the tertiary structure of the active IRES structure, which leads to enhanced translation and replication. It turned out to be important.

Academic Significance and Societal Importance of the Research Achievements

HCV患者で高率に見られる肝外病変の発症メカニズムについて、これまであまり注目されてこなかった、非肝臓細胞でのHCV複製に注目して研究を行った。非肝臓細胞でのHCVの持続感染には変異ウイルスの出現も関与しているが、それに加えて本研究では、肝臓以外でも発現しているマイクロRNAによるウイルス複製のサポートがあることを示し、新たな知見を得た。今後効果的なウイルスの排除法の検討と、肝外病変の発症やウイルス排除後の再燃を制御する有効な治療法の開発に繋がると期待される。

Research Products

• [Int'l Joint Research] Penn State College of Medicine(米国)
• [Journal Article] Various miRNAs compensate the role of miR-122 on HCV replication. (2020)
  • Author(s): Ono C, Fukuhara T, Li S, Wang J, Sato A, Izumi T, Fauzyah Y, Yamamoto T, Morioka Y, Dokholyan NV, Standley DM, Matsuura Y.A3:J3
  • Journal Title: PLoS Pathog Volume: 16 Issue: 6 Pages: e1008308-e1008308
  • DOI: 10.1371/journal.ppat.1008308
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] USP15 Participates in Hepatitis C Virus Propagation through Regulation of Viral RNA Translation and Lipid Droplet Formation (2019)
  • Author(s): Kusakabe S、Suzuki T、Sugiyama Y、Haga S、Horike K、Tokunaga M、Hirano J、Zhang H、Chen DV、Ishiga H、Komoda Y、Ono C、Fukuhara T、Yamamoto M、Ikawa M、Satoh T、Akira S、Tanaka T、Moriishi Ki、Fukai M、Taketomi A、Yoshio S、Kanto T、Suzuki T、Okamoto T、Matsuura Y
  • Journal Title: Journal of Virology Volume: 93 Issue: 6 Pages: 1708-1718
  • DOI: 10.1128/jvi.01708-18
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Induction of selective autophagy in cells replicating hepatitis C virus genome (2018)
  • Author(s): Mori Hiroyuki、Fukuhara Takasuke、Ono Chikako、Tamura Tomokazu、Sato Asuka、Fauzyah Yuzy、Wada Masami、Okamoto Toru、Noda Takeshi、Yoshimori Tamotsu、Matsuura Yoshiharu
  • Journal Title: Journal of General Virology Volume: 99 Issue: 12 Pages: 1643-1657
  • DOI: 10.1099/jgv.0.001161
  • Peer Reviewed / Open Access
• [Presentation] Characterization of mutation in the 5’UTR of HCV in miR-122-dependent propagation (2019)
  • Author(s): Chikako Ono, Takasuke Fukuhara, Yuzy Fauzyah, Shiho Torii, Asuka Sato, Takuma Izumi, Takuya Yamamoto, Yuhei Morioka, and Yoshiharu Matsuura
  • Organizer: 第67回日本ウイルス学会
• [Presentation] Involvement of various miRNAs for an efficient replication of HCV (2019)
  • Author(s): Chikako Ono, Takasuke Fukuhara, Yuzy Fauzyah, Shiho Torii, Asuka Sato, Takuma Izumi, Takuya Yamamoto, Yuhei Morioka, and Yoshiharu Matsuura
  • Organizer: 24th International Symposium on Heepatitis C Virus and Related Viruses
  • Int'l Joint Research
• [Presentation] Involvement of various miRNAs for an efficient replication of HCV (2019)
  • Author(s): Chikako Ono, Takasuke Fukuhara, Tomokazu Tamura, Hiroyuki Mori, Asuka Sato, Takuma Izumi, Yuzy Fauzyah, Toru Okamoto, and Yoshiharu Matsuura
  • Organizer: The 18th Awaji International Forum on Infection and Immunity
  • Int'l Joint Research
• [Presentation] Involvement of various miRNAs for an efficient replication of HCV (2019)
  • Author(s): Chikako Ono, Takasuke Fukuhara, Tomokazu Tamura, Hiroyuki Mori, Asuka Sato, Takuma Izumi, Yuzy Fauzyah, Toru Okamoto, and Yoshiharu Matsuura
  • Organizer: The 38th American Society of Virology 2019 Annual Meeting
  • Int'l Joint Research
• [Presentation] Identification of comparable miRNAs with miR-122 on the propagation of hepatitis C virus. (2018)
  • Author(s): Ono, C., Fukuhara, T., Tamura, T., Mori, H., Sato, A., Fauzyah, Y., Okamoto, T., Chayama, K., Koike, K. and Matsuura, Y.
  • Organizer: 第66回日本ウイルス学会
  • Int'l Joint Research
• [Presentation] miRNAs comparable with miR-122 on the propagation of hepatitis C virus. (2018)
  • Author(s): Ono, C., Fukuhara, T., Okuzaki, D., Tamura, T., Mori, H., Sato, A., Fauzyah, Y., Okamoto, T., Koike, K. and Matsuura, Y.
  • Organizer: The 25th International Symposium on Hepatitis C Virus and Related Viruses
  • Int'l Joint Research