ウイルス潜伏感染の生物学的意義

• Project Area: Neo-virology: the raison d'etre of viruses
• Project/Area Number: 16H06433
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The University of Tokyo
• Principal Investigator: 川口 寧 東京大学, 医科学研究所, 教授 (60292984)
• Project Period (FY): 2016-06-30 – 2021-03-31
• Project Status: Granted (Fiscal Year 2020)
• Budget Amount: ¥140,920,000 (Direct Cost: ¥108,400,000、Indirect Cost: ¥32,520,000); Fiscal Year 2020: ¥25,740,000 (Direct Cost: ¥19,800,000、Indirect Cost: ¥5,940,000); Fiscal Year 2019: ¥26,130,000 (Direct Cost: ¥20,100,000、Indirect Cost: ¥6,030,000); Fiscal Year 2018: ¥25,740,000 (Direct Cost: ¥19,800,000、Indirect Cost: ¥5,940,000); Fiscal Year 2017: ¥26,130,000 (Direct Cost: ¥20,100,000、Indirect Cost: ¥6,030,000); Fiscal Year 2016: ¥37,180,000 (Direct Cost: ¥28,600,000、Indirect Cost: ¥8,580,000)
• Keywords: ウイルス / HSV / 潜伏感染 / 共生維持機構 / 免疫回避機構 / 感染症 / ウィルス

Outline of Annual Research Achievements

本研究領域の目的である「従来、病原性因子の一つとして捉えられているウイルスを、地球生態系の構成因子として捉え直し、地球生態系の恒常性維持機構に果たす意義を解明する」を鑑み、宿主に終生潜伏感染するという高度な共生関係を確立している単純ヘルペスウイルス(HSV)をモデルとして、宿主との共生の成立・維持機構を解析する。さらに、HSV潜伏感染と腸内細菌叢の相互作用に着目し、HSVを恒常性制御因子として捉えることでHSVによる感染享受の生理学的意義を多面的に解析することを目的としている。
本年度は、HSVと宿主との共生維持機構に関して解析を行った。その結果、宿主との共生維持に重要と考えられるウイルス粒子形成機構を明らかにした。具体的には、HSVのヌクレオカプシドは核内で形成され、その後に核内膜をエンベロープとして被り、核内膜から核内外膜腔に出芽する。次にエンベロープと核外膜が融合することでヌクレオカプシドが細胞質に放出される。HSV-1がコードするUL31およびUL34によって構成されるnuclear egress complex(NEC)はこの核膜間のウイルス粒子形成に極めて重要であることが知られている。本年度は以下のことを明らかにした、(i) NECは六量体を形成するが、その六量体間が角膜の変性および核膜間のウイルス粒子形成・ウイルス増殖に重要である。(ii) UL31のα-helix9は、NECとカプシドタンパク質の一つであるUL25と相互作用し、ヌクレオカプシドの核膜間ウイルス粒子への取り込みに重要である。

Current Status of Research Progress

1: Research has progressed more than it was originally planned.

Reason

HSVと宿主との共生維持を可能とするウイルス粒子産生機構には未解明の点が多かった。今回、これらを制御する分子メカニズムの一旦を明らかにし、ウイルス学の代表的な国際学術誌であるJournal of Virologyにおいて発表した。

Strategy for Future Research Activity

本年度に引き続き、HSVの宿主との共生維持機構に関して、現在進行中であるHSVの宿主免疫回避機構や潜伏感染維持機構を中心に解析を行い、その分子メカニズムを明らかにする。また、既に実験系を構築しているマウスにおけるHSV潜伏感染モデルを用いて、HSV潜伏感染の生理学的意義を、腸内細菌叢への影響を基軸として多面的に解析する。

Research Products

• [Journal Article] Identification of the Capsid Binding Site in the Herpes Simplex Virus 1 Nuclear Egress Complex and Its Role in Viral Primary Envelopment and Replication. (2019)
  • Author(s): Takeshima K, Arii J, Maruzuru Y, Koyanagi N, Kato A, Kawaguchi Y.
  • Journal Title: J. Virol. Volume: 93
  • DOI: 10.1128/jvi.01290-19
  • Peer Reviewed / Open Access
• [Journal Article] A role for the CCR5?CCL5 interaction in the preferential migration of HSV-2-specific effector cells to the vaginal mucosa upon nasal immunization (2019)
  • Author(s): Joo Sunyi、Suwanto Aldina、Sato Ayuko、Nakahashi-Ouchida Rika、Mori Hiromi、Uchida Yohei、Sato Shintaro、Kurashima Yosuke、Yuki Yoshikazu、Fujihashi Kohtaro、Kawaguchi Yasushi、Kiyono Hiroshi
  • Journal Title: Mucosal Immunol. Volume: 12 Pages: 1391-1403
  • DOI: 10.1038/s41385-019-0203-z
  • Peer Reviewed / Open Access
• [Journal Article] Roles of the Interhexamer Contact Site for Hexagonal Lattice Formation of the Herpes Simplex Virus 1 Nuclear Egress Complex in Viral Primary Envelopment and Replication. (2019)
  • Author(s): Arii J, Takeshima K, Maruzuru Y, Koyanagi N, Kato A, Kawaguchi Y.
  • Journal Title: J. Virol. Volume: 93
  • DOI: 10.1128/jvi.00498-19
  • Peer Reviewed / Open Access
• [Journal Article] Combating herpesvirus encephalitis by potentiating a TLR3-mTORC2 axis. (2018)
  • Author(s): Sato, R., A. Kato, T. Chimura, S. I. Saitoh, T. Shibata, Y. Murakami, R. Fukui, K. Liu, Y. Zhang, J. Arii, G. H. Sun-Wada. Y. Wada, T. Ikenoue, G. N. Barber, T. Manabe, Y. Kawaguchi, and K. Miyake.
  • Journal Title: Nat. Immunol. Volume: 19 Issue: 10 Pages: 1071-1082
  • DOI: 10.1038/s41590-018-0203-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Roles of the Phosphorylation of Herpes Simplex Virus 1 UL51 at a Specific Site in Viral Replication and Pathogenicity. (2018)
  • Author(s): Kato A, Oda S, Watanabe M, Oyama M, Kozuka-Hata H, Koyanagi N, Maruzuru Y, Arii J, Kawaguchi Y.
  • Journal Title: J Virol Volume: 92
  • DOI: 10.1128/jvi.01035-18
  • Peer Reviewed / Open Access
• [Journal Article] Regulation of Herpes Simplex Virus 2 Protein Kinase UL13 by Phosphorylation and Its Role in Viral Pathogenesis. (2018)
  • Author(s): Koyanagi N, Kato A, Takeshima K, Maruzuru Y, Kozuka-Hata H, Oyama M, Arii J, Kawaguchi Y.
  • Journal Title: J Virol Volume: 92
  • DOI: 10.1128/jvi.00807-18
  • Peer Reviewed / Open Access
• [Journal Article] ESCRT-III mediates budding across the inner nuclear membrane and regulates its integrity. (2018)
  • Author(s): Arii J, Watanabe M, Maeda F, Tokai-Nishizumi N, Chihara T, Miura M, Maruzuru Y, Koyanagi N, Kato A, Kawaguchi Y.
  • Journal Title: Nature Communications Volume: 9 Pages: 3379-3379
  • DOI: 10.1038/s41467-018-05889-9
  • Peer Reviewed / Open Access
• [Journal Article] Herpes Simplex Virus 1 VP22 Inhibits AIM2-Dependent Inflammasome Activation to Enable Efficient Viral Replication. (2018)
  • Author(s): Maruzuru, Y., T. Ichinohe, R. Sato, K. Miyake, T. Okano, T. Suzuki. T. Koshiba, N. Koyanagi, S. Tsuda, M. Watanabe, J. Arii, A. Kato, and Y. Kawaguchi.
  • Journal Title: Cell Host Microbe Volume: 23 Issue: 2 Pages: 254-265
  • DOI: 10.1016/j.chom.2017.12.014
  • Peer Reviewed / Open Access
• [Journal Article] Herpes simplex virus-1 evasion of CD8+ T cell accumulation contributes to viral encephalitis. (2017)
  • Author(s): Koyanagi N, Imai T, Shindo K, Sato A, Fujii W, Ichinohe T, Takemura N, Kakuta S, Uematsu S, Kiyono H, Maruzuru Y, Arii J, Kato A, Kawaguchi Y.
  • Journal Title: Journal of Clinical Investigation Volume: 127 Pages: 3784-3795
  • DOI: 10.1172/jci92931
  • Peer Reviewed / Open Access
• [Journal Article] Complete fusion of a transposon and herpesvirus created the Teratorn mobile element in medaka fish (2017)
  • Author(s): Inoue Y, Saga T, Aikawa T, Kumagai M, Shimada A, Kawaguchi Y, Naruse K, Morishita S, Koga A, Takeda H.
  • Journal Title: Nature Communications Volume: 8 Pages: 551-551
  • DOI: 10.1038/s41467-017-00527-2
  • Peer Reviewed / Open Access
• [Journal Article] Herpes Simplex Virus 1 Small Capsomere-Interacting Protein VP26 Regulates Nucleocapsid Maturation. (2017)
  • Author(s): Kobayashi R, Kato A, Sagara H, Watanabe M, Maruzuru Y, Koyanagi N, Arii J, Kawaguchi Y.
  • Journal Title: J. Virol. Volume: 91
  • DOI: 10.1128/jvi.01068-17
  • Peer Reviewed / Open Access
• [Journal Article] Herpes Simplex Virus 1 UL34 Protein Regulates the Global Architecture of the Endoplasmic Reticulum in Infected Cells. (2017)
  • Author(s): F. Maeda, J. Arii, Y. Hirohata, Y. Maruzuru, N. Koyanagi, A. Kato and Y. Kawaguchi.
  • Journal Title: J Virol. Volume: 印刷中
  • DOI: 10.1128/jvi.00271-17
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 2016 International meeting of the Global Virus Network (2017)
  • Author(s): Akkina Ramesh、Ellerbrok Heinz、Hall William、Hasegawa Hideki、Kawaguchi Yasushi、Kleanthous Harold、McSweegan Edward、Mercer Natalia、Romanowski Victor、Sawa Hirofumi、Vahlne Anders
  • Journal Title: Antiviral Research Volume: 142 Pages: 21-29
  • DOI: 10.1016/j.antiviral.2017.03.005
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Multiple Roles of the Cytoplasmic Domain of Herpes Simplex Virus 1 Envelope Glycoprotein D in Infected Cells. (2016)
  • Author(s): J. Arii, K. Shindo, N. Koyanagi, A. Kato and Y. Kawaguchi.
  • Journal Title: Journal of Virology Volume: 90 Pages: 10170-10181
  • DOI: 10.1128/jvi.01396-16
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Interaction between Herpes Simplex Virus 1 Tegument Proteins UL51 and UL14 and Its Role in Virion Morphogenesis. (2016)
  • Author(s): S. Oda, J. Arii, N. Koyanagi, A. Kato, and Y. Kawaguchi.
  • Journal Title: J Virol. Volume: 90 Pages: 8754-8767
  • DOI: 10.1128/jvi.01258-16
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] UL7 リン酸化制御機構の獲得とαヘルペスウイルス亜科の進化 (2019)
  • Author(s): 柴崎美里, 加藤哲久, 伊東潤平, 菅波麻衣, 竹島功高, 丸鶴雄平, 小栁直人, 有井潤, 佐藤佳, 川口寧
  • Organizer: 第33回ヘルペスウイルス研究会
• [Presentation] Identification of the Capsid Binding Site in the Herpes Simplex Virus 1 Nuclear Egress Complex and Its Role in Viral Primary Envelopment and Replication (2019)
  • Author(s): Kosuke Takeshima, Jun Arii, Yuhei Maruzuru, Naoto Koyanagi, Akihisa Kato, Yasushi Kawaguchi
  • Organizer: 第67回日本ウイルス学会学術集会
• [Presentation] The role of Us3 mediated UL7 phosphorylation during the evolution of α-herpesviruses (2019)
  • Author(s): Misato Shibazaki, Akihisa Kato, Jumpei Ito, Mai Suganami, Kosuke Takeshima, Yuhei Maruzuru, Naoto Koyanagi, Jun Arii, Kei Sato, Yasushi Kawaguchi
  • Organizer: 第67回日本ウイルス学会学術集会
• [Presentation] ワクチン開発を目指した単純ヘルペスウイルスの宿主免疫回避機構の解明 (2019)
  • Author(s): 川口 寧
  • Organizer: 第49回日本皮膚免疫アレルギー学会総会学術大会
  • Invited
• [Presentation] Evolutionary analysis of UL7 phosphorylation events encoded by α-herpesviruses (2019)
  • Author(s): Misato Shibazaki, Akihisa Kato, Jumpei Ito, Mai Suganami, Kosuke Takeshima, Yuhei Maruzuru, Naoto Koyanagi, Jun Arii, Kei Sato, and Yasushi Kawaguchi
  • Organizer: 第18回あわじ感染と免疫国際フォーラム
  • Int'l Joint Research
• [Presentation] Negative regulation of HSV-1 Us3 kinase by tyrosine phosphorylation and its role in viral replication and pathogenesis (2018)
  • Author(s): Nami Kimura, Akihisa Kato, Yuhei Maruzuru, Naoto Koyanagi, Jun Arii, Yasushi Kawaguchi
  • Organizer: 第66回日本ウイルス学会学術集会
• [Presentation] Novel Evasion Mechanisms against Innate and Adaptive Immune Responses by Herpes Simplex Virus 1 (2018)
  • Author(s): Yasushi Kawaguchi
  • Organizer: 43rd Annual International Herpesvirus Workshop
  • Int'l Joint Research / Invited
• [Presentation] 単純ヘルペスウイルスの病態発現機構 (2018)
  • Author(s): 川口 寧
  • Organizer: 一般財団法人日本生物科学研究所第二研究会
  • Invited
• [Presentation] 単純ヘルペスウイルスの新しい宿主免疫回避機構 (2018)
  • Author(s): 川口 寧
  • Organizer: 「感染、免疫、がん、炎症」研究集会
  • Invited
• [Presentation] 単純ヘルペスウイルス（HSV）の細胞間伝播を促進する宿主細胞膜タンパク質の同定 (2017)
  • Author(s): 渡邉瑞季, 有井潤, 下島昌幸, 加藤哲久, 川口寧
  • Organizer: 第14回ウイルス学キャンプ in 湯河原
• [Presentation] HSV-1 UL51 リン酸化制御機構と細胞種依存的な新規機能の解明 (2017)
  • Author(s): 尾田真也, 加藤哲久, 丸鶴雄平, 小栁直人, 有井潤, 川口寧
  • Organizer: 第31回ヘルペスウイルス研究会
• [Presentation] 単純ヘルペスウイルス1型UL34は小胞体の形態制御を行い、ヌクレオカプシドの核出芽輸送制御因子の核膜への集積に関与する (2017)
  • Author(s): 前田史雄, 廣畑吉崇, 有井潤, 加藤哲久, 川口寧
  • Organizer: 第31回ヘルペスウイルス研究会
• [Presentation] 単純ヘルペスウイルス(HSV)の細胞間感染を促進する宿主タンパク質の同定 (2017)
  • Author(s): 渡邉瑞季, 有井潤, 下島昌幸, 加藤哲久, 川口寧
  • Organizer: 第31回ヘルペスウイルス研究会
• [Presentation] 単純ヘルペスウイルスgEと相互作用して細胞間感染を促進する宿主因子の同定 (2017)
  • Author(s): 渡邉瑞季, 有井潤, 下島昌幸, 川口寧
  • Organizer: 第160回日本獣医学会学術集会
• [Presentation] Cell type-specific regulation of the nuclear egress of herpes simplex virus type1 by phosphorylation of UL51 Ser-184 (2017)
  • Author(s): Shinya Oda, Akihisa Kato, Yuhei Maruzuru, Naoto Koyanagi, Jun Arii, Yasushi Kawaguchi
  • Organizer: 第65回日本ウイルス学会学術集会
• [Presentation] A host cell membrane protein interacts with HSV-1 gE and promotes viral cell-to-cell spread (2017)
  • Author(s): Mizuki Watanabe, Jun Arii, Masayuki Shimojima, Akihisa Kato, Yasushi Kawaguchi
  • Organizer: 第65回日本ウイルス学会学術集会
• [Presentation] Identification of a host cell membrane protein that interacts with HSV-1 gE and promotes viral cell-to-cell spread (2017)
  • Author(s): Mizuki Watanabe, Jun Arii, Masayuki Shimojima, Naoto Koyanagi, Yuhei Maruzuru, Akihisa Kato and Yasushi Kawaguchi
  • Organizer: 42nd Annual International Herpesvirus Workshop
  • Int'l Joint Research
• [Presentation] Herpes Simplex Virus 1(HSV-1) UL34 Protein Regulates the Global Architecture of the Endoplasmic Reticulum in Infected Cells. (2017)
  • Author(s): Fumio Maeda
  • Organizer: 24th East Asia Joint Symposium
  • Int'l Joint Research
• [Presentation] Herpes simplex virus type 1 UL51 Protein Regulates Virion Morphogenesis in the Nucleus in a Cell type and Phosphorylation-Dependent Manner (2017)
  • Author(s): Shinya Oda, Akihisa Kato, Naoto Koyanagi, Yuhei Maruzuru, Jun Arii and Yasushi Kawaguchi
  • Organizer: 42nd Annual International Herpesvirus Workshop
  • Int'l Joint Research
• [Presentation] Herpes simplex 1 UL34 Protein Regurates the Global Architecture of the Endoplasmic Reticulum in Infected Cells (2017)
  • Author(s): Fumio Maeda, Jun Arii, Yuhei Maruzuru, Naoto Koyanagi, Akihisa Kato and Yasushi Kawaguchi
  • Organizer: 42nd Annual International Herpesvirus Workshop
  • Int'l Joint Research
• [Presentation] Impact of phosphorylation of two viral proteins on the herpes simplex virus-life cycle in vitro and in vivo (2017)
  • Author(s): Akihisa Kato, Yasushi Kawaguchi
  • Organizer: 9th Inhibitors of Protein Kinases Conference (IPK2017)
  • Int'l Joint Research
• [Presentation] Virus-encoded kinases (2017)
  • Author(s): Yasushi Kawaguchi
  • Organizer: 9th Inhibitors of Protein Kinases Conference (IPK2017)
  • Int'l Joint Research / Invited
• [Presentation] HSV-1 nucleocapsid maturation is regulated by small capsid protein VP26 (2016)
  • Author(s): Ryosuke Kobayashi, Akihisa Kato, Jun Arii, Yasushi Kawaguchi
  • Organizer: 第64回日本ウイルス学会学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道札幌市）
  • Year and Date: 2016-10-23
• [Presentation] HSV-1 UL34 is required for proper targeting of viral and cellular regulators for viral de-envelopment at the nuclear membrane (2016)
  • Author(s): Fumio Maeda, Yoshitaka Hirohata, Jun Arii, Akihisa Kato, Yasushi Kawaguchi
  • Organizer: 第64回日本ウイルス学会学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道札幌市）
  • Year and Date: 2016-10-23
• [Presentation] Enzymatic activity of HSV-1 UNG and viral pathogenesis are regulated by its phosphorylation at a specific site (2016)
  • Author(s): Hayato Harima, Akihisa Kato, Mizuki Watanabe, Jun Arii, Yasushi Kawaguchi
  • Organizer: 第64回日本ウイルス学会学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道札幌市）
  • Year and Date: 2016-10-23
• [Presentation] Cell factors involved in a unique nuclear-pore-independent nuclear export system for macromolecular complexes in the nucleus: Potential targets for novel anti-herpetic drugs (2016)
  • Author(s): Yasushi Kawaguchi
  • Organizer: the 8th International Global Virus Network Meeting
  • Place of Presentation: 札幌コンベンションセンター（北海道札幌市）
  • Year and Date: 2016-10-23
  • Int'l Joint Research / Invited
• [Presentation] Herpes simplex virus 1 VP26 is a regulator of nucleocapsid maturation (2016)
  • Author(s): Ryosuke Kobayashi, Akihisa Kato, Jun Arii, Yasushi Kawaguchi
  • Organizer: The 15th Awaji International Forum on Infection and Immunity
  • Place of Presentation: 淡路夢舞台国際会議場（兵庫県淡路市）
  • Year and Date: 2016-09-06
  • Int'l Joint Research
• [Presentation] HSV UNG phosphorylation at a specific site regulates its enzymatic activity and viral pathogenesis (2016)
  • Author(s): Hayato Harima, Akihisa Kato, Mizuki Watanabe, Jun Arii, Yasushi Kawaguchi
  • Organizer: 第5回感染症若手フォーラム
  • Place of Presentation: 淡路夢舞台国際会議場（兵庫県淡路市）
  • Year and Date: 2016-09-04
• [Presentation] Global monitoring of newly synthesized proteins induced by herpesvirus infection, using BONCAT coupled with mass spectrometry based proteomics technology, unveils novel viral coding DNA sequences (2016)
  • Author(s): Akihisa Kato and Yasushi Kawaguchi
  • Organizer: Nascent Chain Biology Meeting 2016（「新生鎖の生物学」国際会議）
  • Place of Presentation: 富士レークホテル（山梨県南都留郡富士河口湖町）
  • Year and Date: 2016-09-01
  • Int'l Joint Research / Invited
• [Presentation] ESCRT-III mediates HSV-1 Nuclear Egress (2016)
  • Author(s): Jun Arii, Fumio Maeda, Akihisa Kato, Yasushi Kawaguchi
  • Organizer: 41st Annual International Herpesvirus Workshop
  • Place of Presentation: Madison, Wisconsin (USA)
  • Year and Date: 2016-07-23
  • Int'l Joint Research
• [Presentation] HSV-1 VP26 is a Regulator of Nucleocapsid Maturation (2016)
  • Author(s): Ryosuke Kobayashi, Akihisa Kato, Jun Arii, Yasushi Kawagushi
  • Organizer: 41st Annual International Herpesvirus Workshop
  • Place of Presentation: Madison, Wisconsin (USA)
  • Year and Date: 2016-07-23
  • Int'l Joint Research
• [Presentation] Strategies of herpesviruses to hijack host cell machinery (2016)
  • Author(s): Yasushi Kawaguchi
  • Organizer: 感染症研究グローバルネットワークフォーラム2016
  • Place of Presentation: 千葉大学附属病院 ガーネットホール（千葉県千葉市）
  • Invited
• [Remarks] 東京大学医科学研究所 感染・免疫部門 ウイルス病態制御分野
  • URL: http://www.ims.u-tokyo.ac.jp/Kawaguchi-lab/KawaguchiLabTop.html