Research on pathogen recognition and evasion of EB virus

• Project/Area Number: 21K15449
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49060:Virology-related
• Research Institution: Nagoya University
• Principal Investigator: Watanabe Takahiro 名古屋大学, 医学系研究科, 助教 (10624398)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2023: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000); Fiscal Year 2022: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2021: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: EBV / 自然免疫 / STING / cGAS / 免疫回避 / DNAセンサー / 自然免疫応答 / リンパ増殖性疾患 / Epstein-Barr virus / PAMPs / EBV-LPD

Outline of Research at the Start

Epstein-Barr virus (EBV) は、生体防御を担う免疫応答を巧みにコントロールし、免疫平衡の状態で生涯感染を維持することができる。この免疫平衡状態が何らかの理由で破綻すると、EBV関連がんを発症する。本研究では、EBV遺伝子発現ライブラリを用いて特に自然免疫制御機構に着目したスクリーニングを行い、この過程に関わるウイルス因子を同定する。さらに同定したウイルス因子を標的とした遺伝子組換えウイルスを構築し、EBVの造腫瘍性を再現したヒト化マウスモデルを用いたin vivoでの検証を実施し、生体におけるEBVと自然免疫との共進化および発がん機構の解明を推進する。

Outline of Final Research Achievements

Epstein-Barr virus (EBV) causes approximately 200,000 new cancer cases annually worldwide. In this study, we found that viral membrane fusion proteins suppress innate immune responses by binding to the innate immune molecule STING. Additionally, we discovered a molecular mechanism for suppressing STING multimerization via cleavage of membrane fusion proteins. Moreover, preliminary studies have revealed similarities between EBV and other envelope viruses, such as SARS-CoV-2.

Academic Significance and Societal Importance of the Research Achievements

本研究では膜融合タンパク質に秘める免疫抑制機序について解明することによって広域抗ウイルス薬の開発につなげる知見を提供し、自然免疫応答のon/offを運命づける普遍的な現象の発見に繋がる。

Research Products

• [Journal Article] Epstein-Barr virus lytic gene BNRF1 promotes B-cell lymphomagenesis via IFI27 upregulation (2024)
  • Author(s): Sagou Ken、Sato Yoshitaka、Okuno Yusuke、Watanabe Takahiro、Inagaki Tomoki、Motooka Yashiro、Toyokuni Shinya、Murata Takayuki、Kiyoi Hitoshi、Kimura Hiroshi
  • Journal Title: PLOS Pathogens Volume: 20 Issue: 2 Pages: e1011954-e1011954
  • DOI: 10.1371/journal.ppat.1011954
  • Peer Reviewed / Open Access
• [Journal Article] Growth Transformation of B Cells by Epstein-Barr Virus Requires <i>IMPDH2</i> Induction and Nucleolar Hypertrophy (2023)
  • Author(s): Sugimoto Atsuko、Watanabe Takahiro、Matsuoka Kazuhiro、Okuno Yusuke、Yanagi Yusuke、Narita Yohei、Mabuchi Seiyo、Nobusue Hiroyuki、Sugihara Eiji、Hirayama Masaya、Ide Tomihiko、Onouchi Takanori、Sato Yoshitaka、Kanda Teru、Saya Hideyuki、Iwatani Yasumasa、Kimura Hiroshi、Murata Takayuki
  • Journal Title: Microbiology Spectrum Volume: 11 Issue: 4
  • DOI: 10.1128/spectrum.00440-23
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Epstein-Barr Virus BBLF1 Mediates Secretory Vesicle Transport to Facilitate Mature Virion Release (2023)
  • Author(s): Uddin Md Kamal、Watanabe Takahiro、Arata Masataka、Sato Yoshitaka、Kimura Hiroshi、Murata Takayuki
  • Journal Title: Journal of Virology Volume: 97 Issue: 6
  • DOI: 10.1128/jvi.00437-23
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive Analyses of Intraviral Epstein-Barr Virus Protein-Protein Interactions Hint Central Role of BLRF2 in the Tegument Network (2022)
  • Author(s): Hara Yuya、Watanabe Takahiro、Yoshida Masahiro、Masud H. M. Abdullah Al、Kato Hiromichi、Kondo Tomohiro、Suzuki Reiji、Kurose Shutaro、Uddin Md. Kamal、Arata Masataka、Miyagi Shouhei、Yanagi Yusuke、Sato Yoshitaka、Kimura Hiroshi、Murata Takayuki
  • Journal Title: Journal of Virology Volume: 96 Issue: 14
  • DOI: 10.1128/jvi.00518-22
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Genome-wide CRISPR screen for HSV-1 host factors reveals PAPSS1 contributes to heparan sulfate synthesis (2022)
  • Author(s): Suzuki Takeshi、Sato Yoshitaka、Okuno Yusuke、Goshima Fumi、Mikami Tadahisa、Umeda Miki、Murata Takayuki、Watanabe Takahiro、Watashi Koichi、Wakita Takaji、Kitagawa Hiroshi、Kimura Hiroshi
  • Journal Title: Communications Biology Volume: 5 Issue: 1 Pages: 694-694
  • DOI: 10.1038/s42003-022-03581-9
  • Peer Reviewed / Open Access
• [Journal Article] Epstein-Barr virus tegument protein BGLF2 in exosomes released from virus-producing cells facilitates de novo infection (2022)
  • Author(s): Sato Yoshitaka、Yaguchi Masahiro、Okuno Yusuke、Ishimaru Hanako、Sagou Ken、Ozaki Somi、Suzuki Takeshi、Inagaki Tomoki、Umeda Miki、Watanabe Takahiro、Fujimuro Masahiro、Murata Takayuki、Kimura Hiroshi
  • Journal Title: Cell Communication and Signaling Volume: 20 Issue: 1 Pages: 95-95
  • DOI: 10.1186/s12964-022-00902-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PD-L1 upregulation by lytic induction of Epstein-Barr Virus (2022)
  • Author(s): Yanagi Y, Hara Y, Mabuchi S, Watanabe T, Sato Y, Kimura H, Murata T
  • Journal Title: Virology Volume: 568 Pages: 31-40
  • DOI: 10.1016/j.virol.2022.01.006
  • Peer Reviewed
• [Journal Article] A STING inhibitor suppresses EBV‐induced B cell transformation and lymphomagenesis (2021)
  • Author(s): Miyagi Shouhei、Watanabe Takahiro、Hara Yuya、Arata Masataka、Uddin Md. Kamal、Mantoku Keisuke、Sago Ken、Yanagi Yusuke、Suzuki Takeshi、Masud H. M. Abdullah Al、Kawada Jun‐ichi、Nakamura Shigeo、Miyake Yasuyuki、Sato Yoshitaka、Murata Takayuki、Kimura Hiroshi
  • Journal Title: Cancer Science Volume: 112 Issue: 12 Pages: 5088-5099
  • DOI: 10.1111/cas.15152
  • Peer Reviewed / Open Access
• [Presentation] STING inhibitor suppresses EBV-induced B cell transformation and lymphomagenesis (2021)
  • Author(s): Shouhei Miyagi, Takahiro Watanabe, Yuya Hara, Masataka Arata, Md. Kamal Uddin, Yusuke Yanagi, Yoshitaka Sato, Takayuki Murata, Hiroshi Kimura
  • Organizer: 19th International Symposium on Epstein-Barr Virus and associated diseases (EBV2021)
  • Int'l Joint Research
• [Presentation] EBウイルス関連腫瘍のがん微小環境における炎症性細胞浸潤メカニズムの解析 (2021)
  • Author(s): 渡辺 崇広, 佐藤 公治
  • Organizer: 第66回公益社団法人日本口腔外科学会総会・学術大会,幕張メッセ国際会議場