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「長年、病態発現機構に偏重した解析がなされてきたウイルスを、地球生態系の構成要素として捉え直し、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、本研究では単純ヘルペスウイルス(HSV: herpes simplex virus)をモデルとして、ヒトにおいて唯一潜伏感染するヘルペスウイルスの宿主との共生の成立・維持機構や感染享受ともいえる潜伏感染の生理学的意義を、腸内細菌叢との相互作用を含め、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産生機構、および宿主の自然免疫との相互作用を明らかにした。具体的には、HSVが宿主のESCRT-III機構を乗っ取って核内膜からの出芽を引き起こすことで効率よく細胞内で増殖していること、また、宿主のmTORC2が二重鎖RNAセンサーであるToll like receptor 3 (TLR3)を制御することでHSV脳炎を抑制していることが明らかになった。

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、およびHSVに応答する自然免疫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、評価の高い国際雑誌(Nature CommunicationsおよびNature Immunology)において発表するとともに、プレスリリースを行い、成果を広報した。

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、HSVの宿主免疫回避機構や感染維持に必要な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、HSV潜伏感染モデルマウスを用いて、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] 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] Y. 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] The 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] 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