先端医療研究センター感染症制御研究部

NEWS

10.20.2023

The article “Hepatoviruses promote very-long-chain fatty acid and sphingolipid synthesis for viral RNA replication and quasi-enveloped virus release”

was published in Science Advances.

https://www.science.org/doi/full/10.1126/sciadv.adj4198?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org

07.12.2023

The article“A versatile method to profile hepatitis B virus DNA integration”

was published in Hepatology Communications.

https://journals.lww.com/hepcomm/fulltext/2023/12010/a_versatile_method_to_profile_hepatitis_b_virus.8.aspx?context=latestarticles

研究内容

感染病態発生機序を研究し、感染症の診断・治療法の開発につなげます。

WHOによると世界には３億人以上の肝炎ウイルス感染者がいると言われています。この肝炎ウイルスの感染により肝硬変や肝がんが起こり、毎年100万人以上の方が亡くなられています。この状況は日本も例外でなく肝炎ウイルス感染症は重大な公衆衛生上の問題となっています。本研究部は、肝炎ウイルスがどのように肝細胞内で持続的に生きながらえ、またその後、肝硬変や肝細胞がんを引き起こすのかを研究していきます。ウイルスが肝細胞に持続的に感染し続けるメカニズム、それに引き続いて病気が発生する仕組みを詳細に調べることで、ウイルスの排除方法、重症化予測、病態進行阻止法の開発の糸口を探っていきます。

村松　正道

感染症制御研究部　部長
神戸大学　客員教授村松　正道（むらまつ・まさみち）E-mail：muramatsu★fbri.org
[★を@に置き換えてください]

Lab Member

Masamichi Muramatsu, MD, PhD, Professor
Tomoyuki Shiota PhD, Research Assistant Professor
Itoe Shiota PhD, Research Associate
Yuko Sasaki, Technical staff
Manami Yamaoka, Technical staff

  • 研究内容
  • 発表論文

研究事業内容、進捗状況及びこれまでの成果、今後の方向性

本研究部は、2021年度より新設された研究部です。今後、研究が進捗し成果が上がれば、情報を更新していきます。

日本では、肝硬変や肝細胞がんを起こす肝炎ウイルスは、B型肝炎ウイルスとC型肝炎ウイルスが２トップになります。B型肝炎ウイルスとC型肝炎ウイルスはそれぞれ、DNAとRNAをゲノムに持つウイルスでウイルス学的には違うウイルスです。後者は、ここ10年で非常に良い抗ウイルス剤が複数実用化され、ウイルスを肝臓から駆除することも現実的なところまで来ています。一方、前者のB型肝炎ウイルスの抗ウイルス剤は、逆転写阻害剤が一般に使用されています。2012年にB型肝炎ウイルスが細胞に感染する際に必要不可欠な感染受容体の発見により、急速にウイルスの肝細胞でのライフサイクル、とりわけ侵入プロセスの理解が進みました。これらの基盤情報をもとにウイルスの侵入を阻害する薬剤が開発され、治療に使われつつあります。

B型肝炎ウイルスは、cccDNAと呼ばれる２本鎖環状DNAを肝細胞の核内に潜ませる能力があります（図１）。逆転写酵素阻害剤は非常に優秀な抗ウイルス剤ですが、残念なことに一旦作られたcccDNAを核から排除できず、治療を中断するとcccDNAを起点としてウイルスが再び作られる可能性があります。新規の侵入阻害剤もやはり同じ弱点を抱えています。従って、cccDNAをいかにコントロールするかが、体内のウイルス排除に極めて重要であり、新規抗ウイルス剤開発の大きな課題となります。

B型肝炎ウイルスによる発ガン細胞の解析から、発ガン細胞の多くがB型肝炎ウイルスのDNAが肝細胞のゲノムDNAに取り込まれた状態（ウイルスゲノム挿入現象）が観察されます（図２）。
この現象については現在のところ、逆転写後に作られた部分一本鎖ウイルスDNA (RC-DNA)、あるいは損傷を受けたcccDNAが、宿主のゲノムに何らかの機序で取り込まれ、安定化されたものと想定されています。
B型肝炎ウイルスは、発がん活性が示唆されている遺伝子(HBx等)を持っています。これらのがん遺伝子が挿入された遺伝子座から恒常的に発現することが、がん化を大きく進めるのではないかと推察されています。

本研究部では、cccDNAがどのように肝細胞内に潜伏するのか、またウイルスゲノム挿入がどのように起こり肝細胞をがん化させるのか、を研究していきます。そこで明らかにした基盤情報をもとに新規診断法、治療薬開発の糸口を見つけたいと考えています。

またcccDNAやウイルスゲノム挿入現象といったテーマ以外にも、さまざまな感染病態研究を手がけていく予定です。まだ始まったばかりの研究部ですが、よろしくお願いします。

発表論文


2022
  1. Hepatitis C virus (HCV)-induced ROS/JNK signaling pathway activates the E3 ubiquitin ligase Itch to promote the release of HCV particles via polyubiquitylation of VPS4A.
    Deng L, Liang Y, Ariffianto A, Matsui C, Abe T, Muramatsu M, Wakita T, Maki M, Shibata H, Shoji I. J Virol. 2022 Jan 19:JVI0181121. doi: 10.1128/JVI.01811-21. Online ahead of print.PMID: 35044214　
  2. Experimental Cross-Species Transmission of Rat Hepatitis E Virus to Rhesus and Cynomolgus Monkeys.
    Yang F, Li Y, Li Y, Jin W, Duan S, Xu H, Zhao Y, He Z, Ami Y, Suzaki Y, Doan YH, Takeda N, Zhang W, Muramatsu M, Li TC.　Viruses. 2022 Jan 29;14(2):293. doi:10.3390/v14020293.
  3. Induction of neutralizing antibodies against hepatitis C virus by a subviral particle-based DNA vaccine.
    Yato K, Matsuda M, Watanabe N, Watashi K, Aizaki H, Kato T, Tamura K, Wakita T, Muramatsu M, Suzuki R.　Antiviral Res. 2022 Feb 20;199:105266. doi: 10.1016/j.antiviral.2022.105266. PMID: 35196560
  4. Development of an intervention system for linkage-to-care and follow-up for hepatitis B and C virus carriers.
    Kikuchi M, Sawabe M, Aoyagi H, Wakae K, Watashi K, Hattori S, Kawabe N, Yoshioka K, Tanaka J, Muramatsu M, Wakita T, Aizaki H.　Hepatol Int. 2022 Feb;16(1):68-80. doi: 10.1007/s12072-021-10269-5. Epub 2021 Dec 2.
  5. Activities of endogenous APOBEC3s and uracil-DNA-glycosylase affect the hypermutation frequency of hepatitis B virus cccDNA
    Kouichi Kitamura , Kento Fukano , Lusheng Que , Yingfang Li, Kousho Wakae , Masamichi Muramatsu J Gen Virol. 2022 Apr;103(4). doi: 10.1099/jgv.0.001732.
  6. Interferon-gamma induced APOBEC3B contributes to Merkel cell polyomavirus genome mutagenesis in Merkel cell carcinoma.
    Que L, Li Y, Dainichi T, Kukimoto I, Nishiyama T, Nakano Y, Shima K, Suzuki T, Sato Y, Horike S, Aizaki H, Watashi K, Kato T, Aly HH, Watanabe N, Kabashima K, Wakae K(*), Muramatsu M(*).　J Invest Dermatol　 2022, Jul;142(7):1793-1803.e11. doi: 10.1016/j.jid.2021.12.019.
  7. The kinesin KIF4 mediates HBV/HDV entry through the regulation of surface NTCP localization and can be targeted by RXR agonists in vitro.
    Gad SA, Sugiyama M, Tsuge M, Wakae K, Fukano K, Oshima M, Sureau C, Watanabe N, Kato T, Murayama A, Li Y, Shoji I, Shimotohno K, Chayama K, Muramatsu M, Wakita T, Nozaki T, Aly HH. PLoS Pathog. 2022 Mar 21;18(3):e1009983. doi: 10.1371/journal.ppat.1009983. eCollection 2022 Mar.　
  8. Structural insights into the bile acid transporter NTCP, the receptor for HBV.
    Jae-Hyun Park, Masashi Iwamoto, Ji-Hye Yun, Tomomi Uchikubo-Kamo, Donghwan Son, Zeyu Jin1, Hisashi Yoshida, Mio Ohki, Naito Ishimoto, Kenji Mizutani, Mizuki Oshima, Masamichi Muramatsu, Takaji Wakita, Mikako Shirouzu, Kehong Liu, Tomoko Uemura, Norimichi Nomura, So Iwata, Koichi Watashi, Jeremy R. H. Tame, Tomohiro Nishizawa, Weontae Lee, Sam-Yong Park
    Nature 　 2022 Jun;606(7916):1027-1031.doi: 10.1038/s41586-022-04857-0. 　
  9. Mongolia Gerbils Are Broadly Susceptible to Hepatitis E Virus.
    Zhang W, Ami Y, Suzaki Y, Doan YH, Muramatsu M, Li TC. Viruses. 2022 May 24;14(6):1125. doi: 10.3390/v14061125.
  10. Novel flavonoid hybrids as potent antiviral agents against hepatitis A: Design, synthesis and biological evaluation.
    Shi S, Zheng X, Suzuki R, Li Z, Shiota T, Wang J, Hirai-Yuki A, Liu Q, Muramatsu M(*), Song SJ(*). Eur J Med Chem. 2022 Aug 5;238:114452. doi: 10.1016/j.ejmech.2022.114452. Epub 2022 May 14.PMID: 35597006
  11. Significant role of host sialylated glycans in the infection and spread of severe acute respiratory syndrome coronavirus 2.
    Saso W, Yamasaki M, Nakakita SI, Fukushi S, Tsuchimoto K, Watanabe N, Sriwilaijaroen N, Kanie O, Muramatsu M, Takahashi Y, Matano T, Takeda M, Suzuki Y, Watashi K.
    PLoS Pathog. 2022 Jun 14;18(6):e1010590. doi: 10.1371/journal.ppat.1010590. eCollection 2022 Jun.PMID: 35700214
  12. RAISING is a high-performance method for identifying random transgene integration sites.
    Wada Y, Sato T, Hasegawa H, Matsudaira T, Nao N, Coler-Reilly ALG, Tasaka T, Yamauchi S, Okagawa T, Momose H, Tanio M, Kuramitsu M, Sasaki D, Matsumoto N, Yagishita N, Yamauchi J, Araya N, Tanabe K, Yamagishi M, Nakashima M, Nakahata S, Iha H, Ogata M, Muramatsu M, Imaizumi Y, Uchimaru K, Miyazaki Y, Konnai S, Yanagihara K, Morishita K, Watanabe T, Yamano Y, Saito M. Commun Biol. 2022 Jun 2;5(1):535. doi: 10.1038/s42003-022-03467-w.
  13. Estrogen induces the expression of EBV lytic protein ZEBRA, a marker of poor prognosis in nasopharyngeal carcinoma.
    Dochi H, Kondo S, Murata T, Fukuyo M, Nanbo A, Wakae K, Jiang WP, Hamabe-Horiike T, Tanaka M, Nishiuchi T, Mizokami H, Moriyama-Kita M, Kobayashi E, Hirai N, Komori T, Ueno T, Nakanishi Y, Hatano M, Endo K, Sugimoto H, Wakisaka N, Juang SH, Muramatsu M, Kaneda A, Yoshizaki T.Cancer Sci. 2022 May 28. doi: 10.1111/cas.15440. Online ahead of print.
  14. Evaluation of Heat Inactivation of Human Norovirus in Freshwater Clams Using Human Intestinal Enteroids.
    Hayashi T, Yamaoka Y, Ito A, Kamaishi T, Sugiyama R, Estes MK, Muramatsu M, Murakami K.　Viruses. 2022 May 10;14(5):1014. doi: 10.3390/v14051014.
  15. Novel Neplanocin A Derivatives as Selective Inhibitors of Hepatitis B Virus with a Unique Mechanism of Action.
    Toyama M, Watashi K, Ikeda M, Yamashita A, Okamoto M, Moriishi K, Muramatsu M, Wakita T, Sharon A, Baba M. Antimicrob Agents Chemother. 2022 Jun 21;66(6):e0207321. doi: 10.1128/aac.02073-21. Epub 2022 May 23.
  16. Fungal Secondary Metabolite Exophillic Acid Selectively Inhibits the Entry of Hepatitis B and D Viruses.
    Kobayashi C, Watanabe Y, Oshima M, Hirose T, Yamasaki M, Iwamoto M, Iwatsuki M, Asami Y, Kuramochi K, Wakae K, Aizaki H, Muramatsu M, Sureau C, Sunazuka T, Watashi K. Viruses. 2022 Apr 6;14(4):764. doi: 10.3390/v14040764.
  17. Isolation and genome sequencing of hepatitis E virus genotype 1 imported from India to Japan.
    Kobayashi S, Mori A, Sugiyama R, Li TC, Fujii Y, Yato K, Matsuda M, Shiota T, Katsumata M, Iwamoto T, Muramatsu M, Suzuki R .　Jpn J Infect Dis. 2022 Jun 30. doi: 10.7883/yoken.JJID.2022.127. Online ahead of print.PMID: 35768276
  18. Prediction of hand, foot, and mouth disease epidemics in Japan using a long short-term memory approach.
    Yoshida K, Fujimoto T, Muramatsu M, Shimizu H. PLoS One. 2022 Jul 28;17(7):e0271820. doi: 10.1371/journal.pone.0271820. eCollection 2022.PMID: 35900968
  19. Interferon-alpha responsible EPN3 regulates hepatitis B virus replication.
    Li X, Wang Z, Zhou W, Fu X, Zhang Y, Sun Y, Yang B, Bai Y, Dai C, Xu X, Cui F, Zhao Y, Zhang Y, Wang B, Li Y, Muramatsu M, Wakae K, Liu G. Front Med (Lausanne). 2022 Jul 22;9:944489. doi: 10.3389/fmed.2022.944489. eCollection 2022.PMID: 35935763
  20. Neutralization of hepatitis B virus with vaccine-escape mutations by hepatitis B vaccine with large-HBs antigen.
    Washizaki A, Murayama A, Murata M, Kiyohara T, Yato K, Yamada N, Aly HH, Tanaka T, Moriishi K, Nishitsuji H, Shimotohno K, Goh Y, Ishii KJ, Yotsuyanagi H, Muramatsu M, Ishii K, Takahashi Y, Suzuki R, Akari H, Kato T.
    Nat Commun. 2022 Sep 5;13(1):5207. doi: 10.1038/s41467-022-32910-z.PMID: 36064848
  21. Macrophage Depletion Reactivates Fecal Virus Shedding following Resolution of Acute Hepatitis A in Ifnar1-/- Mice.
    Shiota T, Matsuda M, Zheng X, Nagata N, Ishii K, Suzuki R, Muramatsu M, Takimoto K, Hanaki KI, Lemon SM, McGivern DR, Hirai-Yuki A. J Virol. 2022 Nov 10:e0149622. doi: 10.1128/jvi.01496-22. Online ahead of print.PMID: 36354341
  22. Independent evolution of multi-dominant viral genome species observed in a hepatitis C virus carrier.
    Ando T, Aizaki H, Sugiyama M, Date T, Hayashi K, Ishigami M, Katano Y, Goto H, Mizokami M, Muramatsu M, Kuroda M, Wakita T.Biochem Biophys Rep. 2022 Aug 29;32:101327. doi: 10.1016/j.bbrep.2022.101327. eCollection 2022 Dec.PMID: 36072891
  23. Characterization of a Human Sapovirus Genotype GII.3 Strain Generated by a Reverse Genetics System: VP2 Is a Minor Structural Protein of the Virion.
    Li TC, Kataoka M, Doan YH, Saito H, Takagi H, Muramatsu M, Oka T. Viruses. 2022 Jul 27;14(8):1649. doi: 10.3390/v14081649.PMID: 36016271
  24. Identification of neutralizing epitopes in the preS2 domain of the hepatitis B virus.
    Yato K, Matsuda M, Fukano K, Tanaka T, Moriishi K, Nishitsuji H, Shimotohno K, Tamura K, Wakita T, Muramatsu M, Kato T, Suzuki R. Virus Res. 2023 Jan 2;323:199014. doi: 10.1016/j.virusres.2022.199014. Epub 2022 Nov 26.PMID: 36511290
  25. FOXP4 inhibits squamous differentiation of atypical cells in cervical intraepithelial neoplasia via an ELF3-dependent pathway.
    Matsumoto T, Iizuka T, Nakamura M, Suzuki T, Yamamoto M, Ono M, Kagami K, Kasama H, Wakae K, Muramatsu M, Horike SI, Kyo S, Yamamoto Y, Mizumoto Y, Daikoku T, Fujiwara H.Cancer Sci. 2022 Oct;113(10):3376-3389. doi: 10.1111/cas.15489. Epub 2022 Aug 1.PMID: 35838233
  26. Nonlytic Quasi-Enveloped Hepatovirus Release Is Facilitated by pX Protein Interaction with the E3 Ubiquitin Ligase ITCH.
    Shirasaki T, González-López O, McKnight KL, Xie L, Shiota T, Chen X, Feng H, Lemon SM. J Virol. 2022 Nov 9;96(21):e0119522.
  27. The ZCCHC14/TENT4 complex is required for hepatitis A virus RNA synthesis.
    Li Y, Misumi I, Shiota T, Sun L, Lenarcic EM, Kim H, Shirasaki T, Hertel-Wulff A,
    Tibbs T, Mitchell JE, McKnight KL, Cameron CE, Moorman NJ, McGivern DR, Cullen JM,
    Whitmire JK, Lemon SM. Proc Natl Acad Sci U S A. 2022 Jul 12;119(28):e2204511119.
  28. Genetic Characterization of Human Rabies Vaccine Strain in Japan and Rabies Viruses Related to Vaccine Development from 1940s to 1980s. Horiya M, Posadas-Herrera G, Takayama-Ito M, Yamaguchi Y, Iizuka-Shiota I, Kato H, Okamoto A, Saijo M, Lim CK. Viruses. 2022 Sep 29;14(10). doi: 10.3390/v14102152. PubMed PMID: 36298707; PubMed Central PMCID: PMC9607234.

2023
  1. Seroepidemiology of hepatitis A virus infection in Japan: An area of very low endemicity.
    Kiyohara T, Ishii K, Satake M, Matsubayashi K, Suzuki R, Sugiyama R, Sunagawa T, Muramatsu M. Microbiol Immunol. 2023 Jan;67(1):14-21. doi: 10.1111/1348-0421.13035.
  2. Androgen promotes squamous differentiation of atypical cells in cervical intraepithelial neoplasia via an ELF3-dependent pathway.
    Matsumoto T, Suzuki T, Nakamura M, Yamamoto M, Iizuka T, Ono M, Kagami K, Kasama H, Kanda T, Sakai Y, Iwadare J, Matsuoka A, Kayahashi K, Wakae K, Muramatsu M, Kyo S, Yamamoto Y, Mizumoto Y, Daikoku T, Fujiwara H. Cancer Med. 2023 Mar 23. doi: 10.1002/cam4.5824.
  3. Amentoflavone inhibits hepatitis B virus infection via the suppression of preS1 binding to host cells.
    Aoki-Utsubo C, Indrasetiawan P, Fukano K, Muramatsu M, Artanti N, Hanafi M, Hotta H, Kameoka M. Microbiol Immunol. 2023 Mar 16. doi: 10.1111/1348-0421.13064.
  4. Distribution of Human Sapovirus Strain Genotypes over the last four Decades in Japan: a Global Perspective.
    Doan YH, Yamashita Y, Shinomiya H, Motoya T, Sakon N, Suzuki R, Shimizu H, Shigemoto N, Harada S, Yahiro S, Tomioka K, Sakagami A, Ueki Y, Komagome R, Saka K, Okamoto-Nakagawa R, Shirabe K, Mizukoshi F, Arita Y, Haga K, Katayama K, Kimura H, Muramatsu M, Oka T. Jpn J Infect Dis. 2023 Mar 31. doi: 10.7883/yoken.JJID.2022.704.
  5. Open Reading Frame 4 Is Not Essential in the Replication and Infection of Genotype 1 Hepatitis E Virus.
    Bai H, Ami Y, Suzaki Y, Doan YH, Muramatsu M, Li TC. Viruses. 2023 Mar 18;15(3):784. doi: 10.3390/v15030784.PMID: 36992492
  6. Hepatocellular organellar abnormalities following elimination of hepatitis C virus.
    Aoyagi H, Iijima H, Gaber ES, Zaitsu T, Matsuda M, Wakae K, Watashi K, Suzuki R, Masaki T, Kahn J, Saito T, El-Kassas M, Shimada N, Kato K, Enomoto M, Hayashi K, Tsubota A, Mimata A, Sakamaki Y, Ichinose S, Muramatsu M, Wake K, Wakita T, Aizaki H. Liver Int. 2023 Jun 13. doi: 10.1111/liv.15624. Online ahead of print.PMID: 37312620
  7. Performance evaluation of in vitro diagnostic kits for hepatitis B virus infection using the regional reference panel of Japan.
    Momose H, Murayama A, Yamada N, Matsubayashi K, Matsuoka S, Ikebe E, Kuramitsu M, Muramatsu M, Kato T, Hamaguchi I. Virol J. 2023 May 10;20(1):93. doi: 10.1186/s12985-023-02054-7.PMID: 37165426
  8. Inhibitory effect of Ephedra herba on human norovirus infection in human intestinal organoids.
    Hayashi T, Murakami K, Ando H, Ueno S, Kobayashi S, Muramatsu M, Tanikawa T, Kitamura M.　Biochem Biophys Res Commun. 2023 Jun 2;671:200-204. doi: 10.1016/j.bbrc.2023.05.127. Online ahead of print.PMID: 37302295
  9. Nationwide epidemiologic and genetic surveillance of hepatitis E in Japan, 2014-2021.
    Sugiyama R, Takahara O, Yahata Y, Kanou K, Nagashima M, Kiyohara T, Li TC, Arima Y, Shinomiya H, Ishii K, Muramatsu M, Suzuki R. J Med Virol. 2023 Jun;95(6):e28886. doi: 10.1002/jmv.28886.PMID: 37350032
  10. Selective inhibition of hepatitis B virus internalization by oxysterol derivatives.
    Oshima M, Stappenbeck F, Ohashi H, Iwamoto M, Fukano K, Kusunoki A, Zheng X, Wang F, Morishita R, Aizaki H, Suzuki R, Muramatsu M, Kuramochi K, Sureau C, Parhami F, Watashi K. Biochem Biophys Res Commun. 2023 Jul 13;675:139-145. doi: 10.1016/j.bbrc.2023.07.014.: 37473528
  11. Neutralizing activity of intravenous immune globulin products against enterovirus D68 strains isolated in Japan.
    Yoshida K, Muramatsu M, Shimizu H. BMC Infect Dis. 2023 Jul 18;23(1):481. doi: 10.1186/s12879-023-08429-z.PMID: 37464326
  12. Viral protease cleavage of MAVS in genetically modified mice with hepatitis A virus infection. 　Sun L, Feng H, Misumi I, Shirasaki T, Hensley L, González-López O, Shiota I, Chou WC, Ting JP, Cullen JM, Cowley DO, Whitmire JK, Lemon SM. 　J Hepatol. 2023 Feb;78(2):271-280. doi: 10.1016/j.jhep.2022.09.013. Epub 2022 Sep 22. PubMed PMID: 36152761.

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