Analysis of replication mechanism of hepatitis E virus using infection-permissive and -nonpermissive cell lines

• Project/Area Number: 16K08825
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Virology
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: Ishii Koji 国立感染症研究所, 品質保証・管理部, 部長 (40280763)
• Research Collaborator: SHIOTA Tomoyuki
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: E型肝炎ウイルス / 複製機構 / 病原性 / 阻害剤 / ウィルス / 感染症 / 微生物 / 細胞・組織 / たん白質

Outline of Final Research Achievements

The purpose of this study was to develop therapeutic agents for hepatitis E by identifying chemical compounds that inhibit hepatitis E virus (HEV) replication. Chemical libraries were screened for the inhibition of HEV replication using HEV replicon. Several compounds were shown to have strong activity to inhibit HEV replication. These compounds are promising agents for chemotherapy of hepatitis E.

Academic Significance and Societal Importance of the Research Achievements

近年の研究から、E型肝炎は希少な輸入感染症ではなく、我が国においても常に流行の危険は存在すると考えられ、日本でも予防、治療研究への真剣な取り組みが必要になってきていると言える。HEVは慢性化しないため、薬剤としては急性期にウイルス増殖を阻害する薬剤が強く望まれる。構築したHEVレプリコンを用いてHEV増殖阻害剤のスクリーニングを行った化合物ライブラリには、すでに実用化されている薬剤のライブラリも存在するため、見出された化合物はすぐに急性E型肝炎治療薬として応用できる可能性がある。また、これらの阻害剤の阻害メカニズムの解析は、HEVの病原性の解析に重要な手がかりとなる可能性がある。

Research Products

• [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 Pages: 1-6
  • DOI: 10.1073/pnas.1811064116
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High prevalence of hepatitis E virus infection among domestic pigs in Ibaraki Prefecture, Japan. (2019)
  • Author(s): Motoya T., Umezawa M., Goto K., Doi I., Nagata N., Ikeda Y., Sakuta A., Sasaki N. and Ishii K.
  • Journal Title: BMC Veterinary Research Volume: 15 Pages: 219-219
  • DOI: 10.1186/s12917-019-1816-x
  • Peer Reviewed
• [Journal Article] Detection of Subgenotype IA and IIIA Hepatitis A Viruses in Rivers Flowing through Metro Manila, the Philippines (2019)
  • Author(s): Bai Huimin、Shiota Tomoyuki、Yoshizaki Sayaka、Saito-Obata Mariko、Malbas, Jr Fedelino F.、Lupisan Socorro P.、Oshitani Hitoshi、Takeda Naokazu、Muramatsu Masamichi、Wakita Takaji、Ishii Koji、Li Tian-Cheng
  • Journal Title: Japanese Journal of Infectious Diseases Volume: 72 Issue: 1 Pages: 53-55
  • DOI: 10.7883/yoken.jjid.2018.148 10.7883/yoken.JJID.2018.148
  • NAID: 130007577801
  • ISSN: 1344-6304, 1884-2836
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Cluster of Hepatitis A Infections Presumed to be Related to Asari Clams and Investigation of the Spread of Viral Contamination from Asari Clams (2019)
  • Author(s): Tsukada R., Ono S., Kobayashi H., Wada Y., Nishizawa K., Fujii M., Takeuchi M., Kuroiwa K., Kobayashi Y., Ishii K. and Nakazawa H.
  • Journal Title: Japanese Journal of Infectious Diseases Volume: 72 Issue: 1 Pages: 44-48
  • DOI: 10.7883/yoken.jjid.2018.279 10.7883/yoken.JJID.2018.279
  • NAID: 130007577808
  • ISSN: 1344-6304, 1884-2836
• [Journal Article] Multiple antiviral activities of the antimalarial and anti-hepatitis C drug candidates N-89 and N-251 (2018)
  • Author(s): Ueda Youki、Gu Weilin、Dansako Hiromichi、Kim Hye-Sook、Yoshizaki Sayaka、Okumura Nobuaki、Ishikawa Tomohiro、Nishitsuji Hironori、Kato Fumihiro、Hishiki Takayuki、Satoh Shinya、Ishii Koji、Masuda Michiaki、Shimotohno Kunitada、Ikeda Masanori、Kato Nobuyuki
  • Journal Title: Biochemistry and Biophysics Reports Volume: 15 Pages: 1-6
  • DOI: 10.1016/j.bbrep.2018.05.007
  • Peer Reviewed / Open Access
• [Journal Article] Equine-like G3 rotavirus strains as predominant strains among children in Indonesia in 2015?2016 (2018)
  • Author(s): Utsumi Takako、Wahyuni Rury Mega、Doan Yen Hai、Dinana Zayyin、Soegijanto Soegeng、Fujii Yoshiki、Juniastuti、Yamani Laura Navika、Matsui Chieko、Deng Lin、Abe Takayuki、Soetjipto、Lusida Maria Inge、Ishii Koji、Shimizu Hiroyuki、Katayama Kazuhiko、Shoji Ikuo
  • Journal Title: Infection, Genetics and Evolution Volume: 61 Pages: 224-228
  • DOI: 10.1016/j.meegid.2018.03.027
  • NAID: 120006541938
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Evaluation of Heating Conditions for Inactivation of Hepatitis E Virus Genotypes 3 and 4. (2018)
  • Author(s): IMAGAWA T, SUGIYAMA R, SHIOTA T, LI TC, YOSHIZAKI S, WAKITA T, AND ISHII K.
  • Journal Title: Journal of Food Protection Volume: 81(6) Pages: 947-952
  • DOI: 10.4315/0362-028x.jfp-17-290
  • Peer Reviewed / Open Access
• [Journal Article] ステロイドパルス療法を施行した遺伝子型IIIAのA型急性肝炎の1例 (2018)
  • Author(s): 堂免和文、田中博文、小野原伸也、石井孝司、高橋和明、下田慎治
  • Journal Title: 肝臓 Volume: 59 Pages: 481-487
  • Peer Reviewed
• [Journal Article] A型肝炎の最新の動向 (2018)
  • Author(s): 神田達郎、松本直樹、中村仁美、山名陽一郎、水谷 卓、高橋 央、金子朋弘、有間修平、金澤芯依、上村慎也、樋口晃久、楡井和重、山上裕晃、松岡俊一、石井孝司、森山光彦
  • Journal Title: 消化器・肝臓内科 Volume: 4 Pages: 135-140
• [Journal Article] Interferon sensitivity-determining region of hepatitis C virus influences virus production and interferon signaling (2018)
  • Author(s): Sugiyama R., Murayama A., Nitta S., Yamada N., Tasaka-Fujita M., Masaki T., Aly H. H., Shiina M., Ryo A., Ishii K., Wakita T. and Kato T.
  • Journal Title: Oncotarget Volume: 9 Pages: 5627-5640
  • DOI: 10.18632/oncotarget.23562
  • Peer Reviewed / Open Access
• [Journal Article] Induction of humoural and cellular immunity by immunisation with HCV particle vaccine in a non-human primate model (2018)
  • Author(s): Yokokawa H., Higashino A., Suzuki S., Moriyama M., Nakamura N., Suzuki T., Suzuki R., Ishii K., Kobiyama K., Ishii KJ., Wakita T., Akari H. and Kato T.
  • Journal Title: Gut Volume: in press Pages: 372-379
  • DOI: 10.1136/gutjnl-2016-312208
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Immunogenicity of aluminum-adsorbed hepatitis A vaccine (Havrix) administered as a third dose after primary doses of Japanese aluminum-free hepatitis A vaccine (Aimmugen) for Japanese travelers to endemic countries (2017)
  • Author(s): Fukushima S., Kiyohara T., Ishii K., Nakano T. and Hamada A.
  • Journal Title: Vaccine Volume: 35 Pages: 6412-6415
  • DOI: 10.1016/j.vaccine.2017.10.002
  • Peer Reviewed / Open Access
• [Journal Article] Genetic and physicochemical analyses of a novel ferret hepatitis E virus, and clinical signs of infection after birth (2017)
  • Author(s): Li T.C., Yoshizaki S., Kataoka M., Ami Y., Suzaki Y., Doan Y.H., Haga K., Ishii K., Takeda N. and Wakita T.
  • Journal Title: Infect, Genet Evol. Volume: 25 Pages: 153-159
  • DOI: 10.1016/j.meegid.2017.03.026
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] B型肝炎疫学の最新状況 (2017)
  • Author(s): 相崎英樹、Zheng Xin、石井孝司、脇田隆字、砂川富正、大石和徳、吉岡健太郎
  • Journal Title: 消化器・肝臓内科 Volume: 1 Pages: 390-397
• [Journal Article] A型肝炎のウイルス学 (2017)
  • Author(s): 結城（平井）明香、石井孝司
  • Journal Title: 医学のあゆみ Volume: 262 Pages: 1257-1263
• [Journal Article] An Outbreak of Acute Hepatitis Caused by Genotype IB Hepatitis A Viruses Contaminating the Water Supply in Thailand (2017)
  • Author(s): Ruchusatsawat K., Wongpiyabovorn J., Kawidam C., Thiemsing L., Sangkitporn S., Yoshizaki S., Tatsumi M., Takeda N. and Ishii K.
  • Journal Title: Intervirology Volume: 59 Pages: 197-203
  • DOI: 10.1159/000455856
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Clinical features and transmission pattern of hepatitis A: an experience from a hepatitis A outbreak caused by two co-circulating genotypes in Sri Lanka (2016)
  • Author(s): Dahanayaka N., Kiyohara T., Agampodi S., Samaraweera P., Kulasooriya G., Ranasinghe J., Semage S., Yoshizaki S., Wakita T. and Ishii K.
  • Journal Title: American Journal of Tropical Medicine and Hygine Volume: 95 Pages: 908-914
  • DOI: 10.4269/ajtmh.16-0221
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Chronic Hepatitis E Infection in a Persistently Immunosuppressed Patient Unable to Be Eliminated after Ribavirin Therapy (2016)
  • Author(s): Miyoshi M., Kakinuma S., Tanabe Y., Ishii K., Li T.C., Wakita T,, Tsuura Y., Watanabe H., Asahina Y., Watanabe M. and Ikeda T.
  • Journal Title: Intern. Med. Volume: 55 Issue: 19 Pages: 2811-2817
  • DOI: 10.2169/internalmedicine.55.7025
  • NAID: 130005605876
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ferret Hepatitis E Virus Infection Induces Acute Hepatitis and Persistent Infection in Ferrets (2016)
  • Author(s): Li Tiancheng, Yang T, Sayaka Yoshizaki, Kataoka M, Ami Y, Suzaki Y, Kishida N, Shirakura M, Imai M, Asanuma H, Takeda N, Wakita T
  • Journal Title: Veterinary Microbiology Volume: 183 Pages: 30-36
  • DOI: 10.1016/j.vetmic.2015.11.014
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The high prevalence of hepatitis E virus infection in wild boars in Ibaraki Prefecture, Japan (2016)
  • Author(s): Motoya T., Nagata N., Komori H., Doi I., Kurosawa M., Keta T., Sasaki N and Ishii K.
  • Journal Title: J. Vet. Med. Sci. Volume: 77 Issue: 12 Pages: 1705-1709
  • DOI: 10.1292/jvms.15-0173
  • NAID: 130005115323
  • ISSN: 0916-7250, 1347-7439
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] E型肝炎の増加と今後の対策 (2016)
  • Author(s): 石井孝司
  • Journal Title: 検査と技術 Volume: 44 Pages: 1138-1141
• [Presentation] Identification of host kinases that regulate hepatitis B virus internalization. (2018)
  • Author(s): Iwamoto M., Saso W., Sugiyama R., Ishii K., Suzuki R., Aizaki H., Ryo A., Ohtani N., Muramatsu M., Iwami S., Tanaka Y., Wakita T. and Watashi K.
  • Organizer: The 66th Annual Meeting of the Japanese Society for Virology
  • Int'l Joint Research
• [Presentation] A型肝炎ワクチン接種後のサロゲートマーカーに関する検討 (2018)
  • Author(s): 福島慎二、清原知子、石井孝司、中野貴司、濱田篤郎
  • Organizer: 第２２回日本ワクチン学会
• [Presentation] カニクイザルでのH7N9 鳥インフルエンザHAタンパク質発現組換えワクシニアワクチンの発症防御効果の検討 (2018)
  • Author(s): 山地賢三郎、安井文彦、伊藤 靖、鈴木紗織、本田智子、山本直樹、真田崇弘、石垣宏仁、石井孝司、小笠原一誠、小原道法
  • Organizer: 第２２回日本ワクチン学会
• [Presentation] 豚におけるE型肝炎ウイルスの感染実態について (2018)
  • Author(s): 本谷 匠、梅澤昌弘、後藤慶子、土井育子、永田紀子、石井孝司
  • Organizer: 平成３０年度関東・東京合同地区獣医師大会・三学会
• [Presentation] 抗マラリア及び抗HCV薬候補N-89とN-251が有する幅広い抗ウイルス活性 (2018)
  • Author(s): 上田優輝、Gu Weilin、團迫浩方、金 惠淑、吉崎佐矢香、奥村暢章、石川知弘、西辻裕紀、加藤文博、日紫喜隆行、佐藤伸哉、石井孝司、増田道明、下遠野邦忠、池田正徳、加藤宣之
  • Organizer: 第２８回抗ウイルス療法学会学術集会
• [Presentation] Prevalence of hepatitis E virus in pigs in Japan. (2017)
  • Author(s): Ishii K., Yoshizaki S., Li T.C. and Wakita T.
  • Organizer: The 65th Annual Meeting of the Japanese Society for Virology
• [Presentation] Investigation of heat conditions to inactivate hepatitis E virus. (2017)
  • Author(s): Sugiyama R., Imagawa T., Shiota T., Li T.C., Yoshizaki S., Wakita T. and Ishii K.
  • Organizer: The 65th Annual Meeting of the Japanese Society for Virology
• [Presentation] A型肝炎の血清疫学 (2017)
  • Author(s): 清原知子、石井孝司、脇田隆字、佐竹正博
  • Organizer: 第２１回日本ワクチン学会
• [Presentation] E型肝炎の最近の動向と対策 (2017)
  • Author(s): 石井孝司
  • Organizer: 平成２９年度岩手県獣医師会公衆衛生部会
  • Invited
• [Presentation] Epidemiological and genetic analyses of recent hepatitis A virus infection in Japan (2016)
  • Author(s): Ishii K.
  • Organizer: The 10th China-Japan-Korea Forum for Communicable Disease Control and Prevention
  • Place of Presentation: Beijing, China
  • Year and Date: 2016-12-19
  • Int'l Joint Research / Invited
• [Presentation] A型肝炎とE型肝炎の動向と対策 (2016)
  • Author(s): 石井孝司
  • Organizer: 平成２８年度新潟県臨床検査技師会研修会
  • Place of Presentation: 新潟市
  • Year and Date: 2016-12-10
  • Invited
• [Presentation] Epidemiology and molecular genetic analysis of hepatitis A in Japan (2016)
  • Author(s): Ishii K.
  • Organizer: 中日合作交流成果報告会
  • Place of Presentation: Guangzhou, China
  • Year and Date: 2016-12-06
  • Int'l Joint Research / Invited
• [Presentation] 日本におけるＡ型肝炎、Ｅ型肝炎の最近の話題 (2016)
  • Author(s): 石井孝司
  • Organizer: 平成２８年度静岡県獣医師会公衆衛生部会
  • Place of Presentation: 静岡市
  • Year and Date: 2016-10-29
  • Invited
• [Presentation] Molecular characterization of the hepatitis E virus receptor candidate. (2016)
  • Author(s): Shiota T., Li T.C., Yoshizaki S., Nishimura Y., Shimizu H., Shimojima M., Saijo M., Wakita T. and Ishii K.
  • Organizer: The 64th Annual Meeting of the Japanese Society for Virology
  • Place of Presentation: Sapporo, Japan
  • Year and Date: 2016-10-23
  • Int'l Joint Research
• [Presentation] Heat inactivation of Hepatitis E virus. (2016)
  • Author(s): Imagawa T., Li T.C., Shiota T.,Yoshizaki S., Ishii K. and Wakita T.
  • Organizer: The 64th Annual Meeting of the Japanese Society for Virology
  • Place of Presentation: Sapporo, Japan
  • Year and Date: 2016-10-23
  • Int'l Joint Research
• [Presentation] ワクチニアウイルスDIs株を母体としたインフルエンザHA組換えワクチンのカニクイザルでの発症防御効果の検討 (2016)
  • Author(s): 宗片圭祐、安井文彦、伊藤 靖、石井孝司、喜田 宏、小笠原一誠、小原道法
  • Organizer: 第２０回日本ワクチン学会
  • Place of Presentation: 東京
  • Year and Date: 2016-10-22
• [Presentation] Characterization of the hepatitis E virus receptor candidate. (2016)
  • Author(s): Shiota T., Li T.C., Yoshizaki S., Nishimura Y., Shimizu H., Shimojima M., Saijo M., Wakita T. and Ishii K.
  • Organizer: 23rd International Meeting on HCV and Related Viruses
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2016-10-11
  • Int'l Joint Research