Molecular basis of liver fibrosis progression in humanized mouse model infected with HBV

• Project/Area Number: 25860574
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: National Center for Global Health and Medicine
• Principal Investigator: Sugiyama Masaya 国立研究開発法人国立国際医療研究センター, その他部局等, 主任研究員 (20612427)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: B型肝炎ウイルス / ヒト化マウス / 肝線維化 / 自然免疫

Outline of Final Research Achievements

A comprehensive analysis of serum protein was determined to discover a responsible factor relating with liver fibrosis using chimeric mouse samples with liver fibrosis of hepatitis B infection. We focused on an innate ligand induced by viral infection. Several candidate proteins were detected as innate ligands. These factors were added in the culture medium of macrophages separated from the mouse liver. Then, inflammatory cytokines such as TNF-alpha, IL-6, and IL-8 were induced by the treatment. We analyzed innate ligand molecules by the comprehensive analysis using serum from chronic hepatitis B (CHB) patients. The data of CHB patients were compared with that of chimeric mouse. Four candidate factors strongly related with liver fibrosis progression were found by selecting common factors between human and mouse model. These functional analyses were determined during the study period.

Research Products

• [Int'l Joint Research] Novimmune SA.(スイス)
• [Journal Article] Indoleamine-2,3-dioxygenase as an effector and an indicator of protective immune responses in patients with acute hepatitis B. (2016)
  • Author(s): Yoshio S, Sugiyama M, Shoji H, Mano Y, Mita E, Okamoto T, Matsuura Y, Okuno A, Takikawa O, Mizokami M, Kanto T.
  • Journal Title: Hepatology Volume: 63 Issue: 1 Pages: 83-94
  • DOI: 10.1002/hep.28282
  • Peer Reviewed
• [Journal Article] Seroepidemiological study of hepatitis B virus markers in Japan (2015)
  • Author(s): Kiyohara T., Ishii K., Sugiyama M., Mizokami M. and Wakita T.
  • Journal Title: Vaccine Volume: 33 Issue: 45 Pages: 6037-6042
  • DOI: 10.1016/j.vaccine.2015.08.034
  • Peer Reviewed
• [Journal Article] Seroprevalence of chronic hepatitis B, as determined from dried blood spots, among children and their mothers in central Lao People's Democratic Republic: A multistage, stratified cluster sampling survey. (2015)
  • Author(s): Komada K, Sugiyama M, Vongphrachanh P, Xeuatvongsa A, Khamphaphongphane B, Kitamura T, Kiyohara T, Wakita T, Oshitani H, Hachiya M.
  • Journal Title: Int J Infect Dis. Volume: - Pages: 21-26
  • DOI: 10.1016/j.ijid.2015.04.020
  • Peer Reviewed
• [Journal Article] Differential expression of CX3CL1 in HBV-replicating hepatoma cells could affect the migration-activity of CX3CR1+ immune cells. (2015)
  • Author(s): Kondo Y, Kimura O, Tanaka Y, Ninomiya M, Iwata T, Kogure T, Inoue J, Sugiyama M, Morosawa T, Fujisaka Y, Shimosegawa T.
  • Journal Title: J Virol. Volume: -
  • Peer Reviewed
• [Journal Article] Negative regulation of hepatitis B virus replication by forkhead box protein A in human hepatoma cells. (2015)
  • Author(s): Okumura N, Ikeda M, Satoh S, Dansako H, Sugiyama M, Mizokami M, Kato N.
  • Journal Title: FEBS Lett. Volume: 589 Issue: 10 Pages: 1112-8
  • DOI: 10.1016/j.febslet.2015.03.022
  • Peer Reviewed
• [Journal Article] Use of nucleotide analogs in patients with chronic hepatitis B in Nepal: A prospective cohort study in a single hospital. (2015)
  • Author(s): Masaki N, Shrestha PK, Nishimura S, Ito K, Sugiyama M, Mizokami M
  • Journal Title: Hepatol Res Volume: Jan 12 Issue: 12 Pages: 1163-1169
  • DOI: 10.1111/hepr.12482
  • Peer Reviewed
• [Journal Article] Dysregulation of retinoic acid receptor diminishes hepatocyte permissiveness to hepatitis B virus infection through modulation of sodium taurocholate cotransporting polypeptide (NTCP) expression. (2015)
  • Author(s): Tsukuda S, Watashi K, Iwamoto M, Suzuki R, Aizaki H, Okada M, Sugiyama M, Kojima S, Tanaka Y, Mizokami M, Li J, Tong S, Wakita T.
  • Journal Title: J Biol Chem. Volume: 290 Issue: 9 Pages: 5673-84
  • DOI: 10.1074/jbc.m114.602540
  • Peer Reviewed / Open Access
• [Journal Article] Ex vivo induction of IFN-λ3 by a TLR7 agonist determines response to Peg-IFN/ ribavirin therapy in chronic hepatitis C patients (2014)
  • Author(s): Murata K, Sugiyama M, Kimura T, Yoshio S, Kanto T, Kirikae I, Saito H, Aoki Y, Hiramine S, Matsui T, Ito K, Korenaga M, Imamura M, Masaki N, Mizokami M
  • Journal Title: J Gastroenterol Volume: 49(1) Issue: 1 Pages: 126-37
  • DOI: 10.1007/s00535-013-0814-1
  • Peer Reviewed
• [Journal Article] Risk factors for long-term persistence of serum hepatitis B surface antigen following acute hepatitis B virus infection in Japanese adults (2014)
  • Author(s): Ito K, Yotsuyanagi H, Yatsuhashi H, Karino Y, Takikawa Y, Saito T, Arase Y, Imazeki F, Kurosaki M, Umemura T, Ichida T, Toyoda H, Yoneda M, Mita E, Yamamoto K, Michitaka K, Maeshiro T, Tanuma J, Tanaka Y, Sugiyama M, Murata K, Masaki N, Mizokami M; Japanese AHB Study Group
  • Journal Title: Hepatology Volume: 59 Issue: 1 Pages: 89-97
  • DOI: 10.1002/hep.26635
  • Peer Reviewed
• [Journal Article] Cyclosporin A and its analogs inhibit hepatitis B virus entry into cultured hepatocytes through targeting a membrane transporter, sodium taurocholate cotransporting polypeptide (NTCP) (2014)
  • Author(s): Watashi K, Sluder A, Daito T, Matsunaga S, Ryo A, Nagamori S, Iwamoto M, Nakajima S, Tsukuda S, Borroto-Esoda K, Sugiyama M, Tanaka Y, Kanai Y, Kusuhara H, Mizokami M, Wakita T
  • Journal Title: Hepatology Volume: 59 Issue: 5 Pages: 1726-1737
  • DOI: 10.1002/hep.26982
  • Peer Reviewed
• [Journal Article] New susceptibility and resistance HLA-DP alleles to HBV-related diseases identified by a trans-ethnic association study in Asia. (2014)
  • Author(s): Nishida N, Sawai H, Kashiwase K, Minami M, Sugiyama M, Seto WK, Yuen MF, Posuwan N, Poovorawan Y, Ahn SH, Han KH, Matsuura K, Tanaka Y, Kurosaki M, Asahina Y, Izumi N, Kang JK, （省略）, Tokunaga K, and Mizokami M
  • Journal Title: PLoS One Volume: 9 Issue: 2 Pages: e86449-e86449
  • DOI: 10.1371/journal.pone.0086449
  • Peer Reviewed / Open Access
• [Journal Article] Chronic Hepatitis B Prevalence among Children and Mothers: Results from a Nationwide, Population-Based Survey in Lao People’s Democratic Republic. (2014)
  • Author(s): Xeuatvongsa A., Komada K., Kitamura T., Vongphrachanh P., Pathammavong C., Phounphenghak K., Sisouk T., Phonekeo D., Sengkeopaseuth B., Som-Oulay V., Ishii K., Wakita T., Sugiyama M. and Hachiya M.
  • Journal Title: PLOS One Volume: 9 Issue: 2 Pages: e88829-e88829
  • DOI: 10.1371/journal.pone.0088829
  • Peer Reviewed
• [Journal Article] IL28B polymorphisms and clinical implications for hepatitis C virus infection in Uzbekistan (2014)
  • Author(s): Khudayberganova D, Sugiyama M, Masaki N, Nishida N, Mukaide M, Sekler D, Latipov R, Nataliya K, Dildora S, Sharapov S, Usmanova G, Raxmanov M, Musabaev E, Mizokami M
  • Journal Title: PLoS One Volume: 24;9 Issue: 3 Pages: e93011-e93011
  • DOI: 10.1371/journal.pone.0093011
  • Peer Reviewed / Open Access
• [Journal Article] Human blood dendritic cell antigen 3 (BDCA3)(+) dendritic cells are a potent producer of interferon-λ in response to hepatitis C virus (2013)
  • Author(s): Yoshio S, Kanto T, Kuroda S, Matsubara T, Higashitani K, Kakita N, Ishida H, Hiramatsu N, Nagano H, Sugiyama M, Murata K, Fukuhara T, Matsuura Y, Hayashi N, Mizokami M, Takehara T
  • Journal Title: Hepatology Volume: 57 Issue: 5 Pages: 1705-15
  • DOI: 10.1002/hep.26182
  • Peer Reviewed
• [Journal Article] 2'-Fluoro-6'-methylene-carbocyclic adenosine phosphoramidate (FMCAP) prodrug : In vitro anti-HBV activity against the lamivudine-entecavir resistant triple mutant and its mechanism of action. (2013)
  • Author(s): Rawal RK, Singh US, Chavre SN, Wang J, Sugiyama M, Hung W, Govindarajan R, Korba B, Tanaka Y, Chu CK.
  • Journal Title: Bioorg Med Chem Lett. Volume: 15 Issue: 2 Pages: 503-6
  • DOI: 10.1016/j.bmcl.2012.11.027
  • Peer Reviewed
• [Journal Article] Specific mutations of basal core promoter are associated with chronic liver disease in hepatitis B virus subgenotype D1 prevalent in Turkey. (2013)
  • Author(s): Sunbul M, Sugiyama M, Kurbanov F, Leblebicioglu H, Khan A, Elkady A, Tanaka Y, Mizokami M.
  • Journal Title: Microbiol Immunol. Volume: 57 Issue: 2 Pages: 122-9
  • DOI: 10.1111/1348-0421.12011
  • Peer Reviewed
• [Journal Article] Tracing the spread of hepatitis C virus in Turkey: a phylogenetic analysis. (2013)
  • Author(s): Sunbul M, Khan A, Kurbanov F, Leblebicioglu H, Sugiyama M, Tanaka Y, Mizokami M.
  • Journal Title: Intervirology. Volume: 56 Issue: 3 Pages: 201-5
  • DOI: 10.1159/000346775
  • Peer Reviewed
• [Journal Article] In vitro replication competence of a hepatitis B genotype D/A recombinant virus: dissimilar biological behaviour regarding its parental genotypes. (2013)
  • Author(s): Trinks J, Sugiyama M, Tanaka Y, Kurbanov F, Benetucci J, Giménez E, Weissenbacher MC, Mizokami M, Oubiña JR.
  • Journal Title: J Gen Virol. Volume: 94 Issue: 12 Pages: 2724-8
  • DOI: 10.1099/vir.0.053595-0
  • Peer Reviewed
• [Journal Article] Hepatitis C virus kinetics by administration of pegylated interferon-lin human and chimeric mice carrying human hepatocytes with variants of the IL28B gene (2012)
  • Author(s): Watanabe T, Sugauchi F, Tanaka Y, Matsuura K, Yatsuhashi H, Murakami S, Iijima S, Iio E, Sugiyama M, Shimada T, Kakuni M, Kohara M, Mizokami M
  • Journal Title: Gut Volume: Nov 7 Issue: 9 Pages: 1340-6
  • DOI: 10.1136/gutjnl-2012-302553
  • Peer Reviewed
• [Presentation] TLR4 signaling mediate liver fibrosis in chimeric mice persistently infected with HBV (2015)
  • Author(s): Masaya Sugiyama, Tatsuya Kanto, and Masashi Mizokami
  • Organizer: The 63rd Annual Meeting of The Japanese Society for Virology
  • Place of Presentation: 福岡
  • Year and Date: 2015-11-23
• [Presentation] Impact of toll-like receptor 4 signaling on liver fibrosis in uPA/SCID mice with human hepatocytes persistently infected with hepatitis B virus (2015)
  • Author(s): Masaya Sugiyama, Tatsuya Kanto, Masaaki Korenaga, Kazumoto Murata, Naohiko Masaki, and Masashi Mizokami
  • Organizer: The Liver Meeting 2015: The 66th Annual Meeting of AASLD
  • Place of Presentation: San Francisco
  • Year and Date: 2015-11-16
  • Int'l Joint Research
• [Presentation] Effect of toll-like receptor 4 signaling on liver fibrosis in uPA/SCID mice with human hepatocytes persistently infected with hepatitis B virus (2015)
  • Author(s): Masaya Sugiyama, Tatsuya Kanto, and Masashi Mizokami
  • Organizer: 2015 International Meeting on Molecular Biology of Hepatitis B Viruses
  • Place of Presentation: Bad Nauheim
  • Year and Date: 2015-10-08
  • Int'l Joint Research
• [Presentation] Incidence of HBV infection in MSM cohort in Ulaanbaatar and new therapies for hepatitis B and C. (2014)
  • Author(s): Masaya Sugiyama
  • Organizer: Japan-Mongolia Collaborative Study for HIV and Hepatitis in MSM in Mongolia.
  • Place of Presentation: Ulaanbaatar
  • Year and Date: 2014-10-23
• [Presentation] Association of sphingolipid biosynthesis pathway as a novel therapeutic target for HBV replication. (2014)
  • Author(s): Masaya Sugiyama, Yasuhito Tanaka, Makoto Nakanishi, Masayuki Sudoh, and Masashi Mizokami.
  • Organizer: 2014 International Meeting on Molecular Biology of Hepatitis B Viruses.
  • Place of Presentation: Los Angels
  • Year and Date: 2014-09-04
• [Presentation] Clinical Significance of Host Factors in Viral Hepatitis (2014)
  • Author(s): Masashi Mizokami, Nao Nishida, and Masaya Sugiyama
  • Organizer: The 2nd International Symposium of Catholic University Liver Research Center Symposium
  • Place of Presentation: Korea
  • Year and Date: 2014-07-26
  • Invited
• [Presentation] 宿主因子を標的とした新規抗B型肝炎ウイルス製剤の開発と作用機序の解析 (2014)
  • Author(s): 杉山真也、田中靖人、溝上雅史
  • Organizer: 第50回日本肝臓学会総会
  • Place of Presentation: ホテルニューオオタニ赤坂
  • Year and Date: 2014-05-30
• [Presentation] B型肝炎ウイルス複製に関連する脂質分子の同定とその効果 (2013)
  • Author(s): 杉山真也、田中靖人、溝上雅史
  • Organizer: 第49回日本肝臓学会総会
  • Place of Presentation: 東京
• [Presentation] Polymorphisms consisting of (TA)n dinucleotide repeat near IL28B gene could improve the predictive value for HCV spontaneous clearance with IL28B SNPs. (2013)
  • Author(s): Masaya Sugiyama, Satoshi Hiramine, Norihiro Furusyo, Akio Ido, Hirohito Tsubouchi, Hisayoshi Watanabe, Yoshiyuki Ueno, Masaaki Korenaga, Kazumoto Murata, Naohiko Masaki, Jun Hayashi, and Masashi Mizokami
  • Organizer: The 64th Annual Meeting of the AASLD
  • Place of Presentation: Washington DC
• [Presentation] Clinical and virological analysis on Hepatitis B virus genotype D (2013)
  • Author(s): Masaya Sugiyama, Yasuhito Tanaka, and Masashi Mizokami
  • Organizer: Japan-Taiwan Research Symposium on Hepatitis B.
  • Place of Presentation: 東京
• [Presentation] Prediction improvement on the effect of interferon-based therapy and spontaneous clearance of hepatitis C using rs72258881 near IL-28B following rs8099917 (2013)
  • Author(s): Masaya Sugiyama, Akio Ido, Hirohito Tsubouchi, Hisayoshi Watanabe, Yoshiyuki Ueno, Kazumoto Murata, Masaaki Korenaga, and Masashi Mizokami
  • Organizer: The International Liver Congress 2013: 48th Annual Meeting of EASL
  • Place of Presentation: Amsterdam