Study of mechanisms of viral PLAMP production and PLAMP-mediated regulation of pathogenicity

• Project Area: Establishment of PLAMP as a new concept to determine self and nonself for obligatory intracellular pathogens
• Project/Area Number: 20H05773
• Research Category: Grant-in-Aid for Transformative Research Areas (B)
• Allocation Type: Single-year Grants
• Review Section: Transformative Research Areas, Section (III)
• Research Institution: Kyoto University
• Principal Investigator: Hashiguchi Takao 京都大学, 医生物学研究所, 教授 (50632098)
• Project Period (FY): 2020-10-02 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥46,150,000 (Direct Cost: ¥35,500,000、Indirect Cost: ¥10,650,000); Fiscal Year 2022: ¥14,950,000 (Direct Cost: ¥11,500,000、Indirect Cost: ¥3,450,000); Fiscal Year 2021: ¥14,950,000 (Direct Cost: ¥11,500,000、Indirect Cost: ¥3,450,000); Fiscal Year 2020: ¥16,250,000 (Direct Cost: ¥12,500,000、Indirect Cost: ¥3,750,000)
• Keywords: 膜融合 / 構造 / エントリー / PLAMP / ウイルス学 / 構造生物学 / 自己・非自己

Outline of Research at the Start

ウイルスは単独では増えることが出来ず、細胞のシステムと一体化することでウイルス自身の増殖を可能にする生存戦略をとっている。すなわち、細胞への侵入(自己化)と細胞からの出芽(非自己化)という過程があり、ウイルスを含む微生物は自身のライフサイクルによって生じる宿主由来分子パターンを細胞上に作り出す。
そこで、本研究では、呼吸器感染症を起こすウイルスをモデル微生物として、分子・細胞 生物学、構造生物学、免疫学、実験動物学の技術を中心とした解析を行い、ウイルス感染に伴う宿主側のミクロな変化を宿主自身が如何にして感知・制御するのか、病原性制御機構の解明を行う。

Outline of Final Research Achievements

In order to elucidate the pathogenic regulatory mechanisms mediated by PLAMP (Pathogen "Life cycle"-Associated Molecular Pattern) during viral infection (cell entry by membrane fusion and budding by membrane fission) using paramyxoviruses and coronaviruses, a combination strategy of structural biology and virological methods were used. As the results, we observed that IFN-inducible molecules, host-derived ligand-like molecules, and carbohydrate chains affect cell entry.

Academic Significance and Societal Importance of the Research Achievements

パラミクソウイルス科は、麻疹（はしか）を起こす麻疹ウイルスや流行性耳下腺炎（おたふくかぜ）の原因であるムンプスウイルスを、コロナウイルス科は重症肺炎などを起こす新型コロナウイルスといった臨床上重要な病原体を含む。従って、これらのウイルスにおけるPLAMPを通じた病原性の理解とその感染制御に関する研究を行うことは、ウイルスへの学問的な理解だけに留まらず、予防・治療法への活用を含めた感染対策として医療や福祉にも貢献が期待できる。

Research Products

• [Int'l Joint Research] Weizmann Institute of Science(その他の国・地域 イスラエル)
• [Int'l Joint Research] University of Naples Federico II(イタリア)
• [Int'l Joint Research] Icahn School of Medicine at Mount Sinai(米国)
• [Int'l Joint Research] マウントサイナイ医科大学/ラホヤアレルギー免疫研究所(米国)
• [Journal Article] Structural basis of spike RBM-specific human antibodies counteracting broad SARS-CoV-2 variants (2023)
  • Author(s): Kiyomi Shitaoka, Akifumi Higashiura, Yohei Kawano, Akima Yamamoto, Yoko Mizoguchi, Takao Hashiguchi , Norihisa Nishimichi, Shiyu Huang, Ayano Ito, Shun Ohki, Miyuki Kanda, Tomohiro Taniguchi, Rin Yoshizato, Hitoshi Azuma, Yasuo Kitajima, Yasuyuki Yokosaki, Satoshi Okada, Takemasa Sakaguchi, Tomoharu Yasuda
  • Journal Title: Communications Biology Volume: 6 Issue: 1 Pages: 1-14
  • DOI: 10.1038/s42003-023-04782-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Application of Acoustic Ejection MS System to High-Throughput Screening for SARS-CoV-2 3CL Protease Inhibitors (2022)
  • Author(s): Hasegawa Tsukasa、Imamura Riyo M.、Suzuki Tateki、Hashiguchi Takao、Nomura Takao、Otsuguro Satoko、Maenaka Katsumi、Sasaki Michihito、Orba Yasuko、Sawa Hirofumi、Sato Akihiko、Okabe Takayoshi、Nagano Tetsuo、Kojima Hirotatsu
  • Journal Title: Chemical and Pharmaceutical Bulletin Volume: 70 Issue: 3 Pages: 199-201
  • DOI: 10.1248/cpb.c21-01003
  • NAID: 130008165547
  • ISSN: 0009-2363, 1347-5223
  • Year and Date: 2022-03-01
  • Peer Reviewed / Open Access
• [Journal Article] Virological characteristics of the SARS-CoV-2 Omicron BA.2 subvariants, including BA.4 and BA.5 (2022)
  • Author(s): Kimura et al.
  • Journal Title: Cell Volume: 185 Issue: 21 Pages: 3992-4007
  • DOI: 10.1016/j.cell.2022.09.018
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Virological characteristics of the SARS-CoV-2 Omicron BA.2.75 variant (2022)
  • Author(s): Saito et al.
  • Journal Title: Cell Host & Microbe Volume: 30 Issue: 11 Pages: 1540-1540
  • DOI: 10.1016/j.chom.2022.10.003
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Fitness selection of hyperfusogenic measles virus F proteins associated with neuropathogenic phenotypes (2021)
  • Author(s): Ikegame Satoshi、Hashiguchi Takao、Hung Chuan-Tien、Dobrindt Kristina、Brennand Kristen J.、Takeda Makoto、Lee Benhur
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 118 Issue: 18
  • DOI: 10.1073/pnas.2026027118
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Unique Tropism and Entry Mechanism of Mumps Virus (2021)
  • Author(s): Kubota Marie、Hashiguchi Takao
  • Journal Title: Viruses Volume: 13 Issue: 9 Pages: 1746-1746
  • DOI: 10.3390/v13091746
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A SARS-CoV-2 antibody broadly neutralizes SARS-related coronaviruses and variants by coordinated recognition of a virus-vulnerable site (2021)
  • Author(s): Onodera T, Kita S, Adachi Y, Moriyama S, Sato A, Nomura T, Sakakibara S, Inoue T, Tadokoro T, Anraku Y, Yumoto K, Tian C, Fukuhara H, Sasaki M, Orba Y, Shiwa N, Iwata N, Nagata N, Suzuki T, others, and Takahashi Y
  • Journal Title: Immunity Volume: 54 Issue: 10 Pages: 2385-2398
  • DOI: 10.1016/j.immuni.2021.08.025
  • Peer Reviewed / Open Access
• [Journal Article] Resistance of SARS-CoV-2 variants to neutralization by antibodies induced in convalescent patients with COVID-19 (2021)
  • Author(s): Kaku Y, Kuwata T, Zahid HM, Hashiguchi T, Noda T, Kuramoto N, Biswas S, Matsumoto K, Shimizu M, Kawanami Y, Shimura K, Onishi C, Muramoto Y, Suzuki T, Sasaki J, Nagasaki Y, Minami R, Motozono C, Toyoda M, Takahashi H, Kishi H, Fujii K, Tatsuke T, Ikeda T, Maeda Y, Ueno T, Koyanagi Y, Iwagoe H, Matsushita S.
  • Journal Title: Cell Reports Volume: 36 Issue: 2 Pages: 109385-109385
  • DOI: 10.1016/j.celrep.2021.109385
  • Peer Reviewed / Open Access
• [Journal Article] Characterization of Natural and Synthetic Sialoglycans Targeting the Hemagglutinin-Neuraminidase of Mumps Virus (2021)
  • Author(s): Forgione Rosa Ester、Di Carluccio Cristina、Milanesi Francesco、Kubota Marie、Fabregat Nieto Ferran、Molinaro Antonio、Hashiguchi Takao、Francesconi Oscar、Marchetti Roberta、Silipo Alba
  • Journal Title: Frontiers in Chemistry Volume: 9 Pages: 711346-711346
  • DOI: 10.3389/fchem.2021.711346
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The physiological TMPRSS2 inhibitor HAI-2 alleviates SARS-CoV-2 infection (2021)
  • Author(s): Tomita Yuriko、Matsuyama Shutoku、Fukuhara Hideo、Maenaka Katsumi、Kataoka Hiroaki、Hashiguchi Takao、Takeda Makoto
  • Journal Title: Journal of Virology Volume: 95 Issue: 12
  • DOI: 10.1128/jvi.00434-21
  • Peer Reviewed / Open Access
• [Journal Article] Viral Biophysics: Contributions to Drug Modalities (2021)
  • Author(s): MAENAKA Katsumi、FUKUHARA Hideo、HASHIGUCHI Takao、CAAVEIRO Jose M. M.、NAGATOISHI Satoshi、KURODA Daisuke、TSUMOTO Kouhei
  • Journal Title: Seibutsu Butsuri Volume: 61 Issue: 2 Pages: 082-089
  • DOI: 10.2142/biophys.61.082
  • NAID: 130008002753
  • ISSN: 0582-4052, 1347-4219
  • Open Access
• [Presentation] 新型コロナウイルス変異株による受容体認識・中和抗体逃避の構造基盤および創薬展開 (2022)
  • Author(s): 橋口隆生
  • Organizer: 2022年度量子ビームサイエンスフェスタ
  • Invited
• [Presentation] Molecular mechanism of neutralization of a pan-SARS-CoV-2 antibody and ACE2-receptor recognition by BA.4/5 variants (2022)
  • Author(s): Hashiguchi T
  • Organizer: The 20th Awaji International Forum on Infection and Immunity (AIFII 20)
  • Int'l Joint Research / Invited
• [Presentation] 蛋白質精製技術を活用したコロナウイルス研究 (2022)
  • Author(s): 橋口隆生
  • Organizer: 第95回日本細菌学会
  • Invited
• [Presentation] Structural biology of human pathogenic RNA viruses (2021)
  • Author(s): Hashiguchi T
  • Organizer: UCLA-KU seminar series
  • Int'l Joint Research / Invited
• [Presentation] Molecular mechanism of glycan receptor recognition by mumps virus (2021)
  • Author(s): Hashiguchi T
  • Organizer: The 27th East Asia Joint Symposium (EAJS)
  • Int'l Joint Research / Invited
• [Presentation] 麻疹ウイルスによる神経感染症の分子メカニズム (2021)
  • Author(s): 橋口隆生
  • Organizer: 第 25 回日本神経感染症学会総会・学術大会
  • Invited
• [Presentation] コロナウイルス研究のための蛋白質科学プラットフォームの構築 (2021)
  • Author(s): 橋口隆生
  • Organizer: 第41回阿蘇シンポジウム
  • Invited
• [Presentation] Glycan receptors for mumps virus and other paramyxoviruses (2020)
  • Author(s): Hashiguchi T
  • Organizer: 2020 Society for Glycobiology Virtual Meeting
  • Int'l Joint Research / Invited
• [Presentation] Identify and interrogating the functional constraints that contribute to the lack of antigenic drift in paramyxoviruses. (2020)
  • Author(s): Satoshi Ikegame, Kasopefoluwa Oguntuyo, Takao Hashiguchi, Makoto Takeda, Benhur Lee
  • Organizer: American Society for Virology (ASV) 39th Annual Meeting
  • Int'l Joint Research