Molecular basis for the inhibition of stress granule formation by rabies virus, a new concept of innate immune evasion mechanism

• Project/Area Number: 17K08083
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Veterinary medical science
• Research Institution: Kagoshima University
• Principal Investigator: Masatani Tatsunori 鹿児島大学, 農水産獣医学域獣医学系, 准教授 (70614072)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 狂犬病 / ストレス顆粒 / 自然免疫

Outline of Final Research Achievements

We confirmed the accumulation of RIG-I in stress granules (SGs) formed by rabies virus attenuated strain infection. The host factor PKR, which is thought to be involved in SG formation, is also involved in SG formation in rabies virus-infected cells. Among the five rabies virus-encoded proteins (N, P, M, G, and L), the M protein was shown to play a major role in SG formation. The M protein of the rabies virus Ni-CE strain is also involved in caspase-independent cell death.

Academic Significance and Societal Importance of the Research Achievements

狂犬病は、重篤な神経症状を主徴とするウイルス性人獣共通感染症である。本病はワクチンによって予防可能であるものの、ひとたび発症した場合の有効な治療法は無く、その致死率は100%にのぼる。しかし、狂犬病ウイルスが高い病原性を示すメカニズムの分子基盤は不明な点が多いのが現状である。本病の治療戦略を開発するうえで、ウイルスがどのように宿主の免疫系を逃れているかを知ることは重要である。本研究では、自然免疫の発動に重要なシステムとして近年発見された「ストレス顆粒形成」を狂犬病ウイルスが抑制することを明らかにした。

Research Products

• [Journal Article] Phylogenetic variations of highly pathogenic H5N6 avian influenza viruses isolated from wild birds in the Izumi plain, Japan, during the 2016?17 winter season (2018)
  • Author(s): Ozawa Makoto、Matsuu Aya、Khalil Ahmed Magdy、Nishi Natsuko、Tokorozaki Kaori、Masatani Tatsunori、Horie Masayuki、Okuya Kosuke、Ueno Kosei、Kuwahara Masakazu、Toda Shigehisa
  • Journal Title: Transboundary and Emerging Diseases Volume: 66 Issue: 2 Pages: 797-806
  • DOI: 10.1111/tbed.13087
  • Peer Reviewed
• [Journal Article] Generation of a novel live rabies vaccine strain with a high level of safety by introducing attenuating mutations in the nucleoprotein and glycoprotein (2017)
  • Author(s): Nakagawa Keisuke、Nakagawa Kento、Omatsu Tsutomu、Katayama Yukie、Oba Mami、Mitake Hiromichi、Okada Kazuma、Yamaoka Satoko、Takashima Yasuhiro、Masatani Tatsunori、Okadera Kota、Ito Naoto、Mizutani Tetsuya、Sugiyama Makoto
  • Journal Title: Vaccine Volume: 35 Issue: 42 Pages: 5622-5628
  • DOI: 10.1016/j.vaccine.2017.08.050
  • Peer Reviewed
• [Journal Article] Genetic characterization of an avian H4N6 influenza virus isolated from the Izumi plain, Japan (2017)
  • Author(s): Okuya Kosuke、Kanazawa Norihiro、Kanda Takehiro、Kuwahara Masakazu、Matsuu Aya、Horie Masayuki、Masatani Tatsunori、Toda Shigehisa、Ozawa Makoto
  • Journal Title: Microbiology and Immunology Volume: 61 Issue: 11 Pages: 513-518
  • DOI: 10.1111/1348-0421.12545
  • NAID: 40021380961
  • Peer Reviewed
• [Presentation] 狂犬病ウイルスM蛋白質95位のアミノ酸が関与する細胞死誘導機構の解析 (2020)
  • Author(s): 児島一州、小澤真、伊藤直人、杉山誠、正谷達謄
  • Organizer: 9th Negative strand virus-Japan symposium
• [Presentation] Investigation of cell death mechanism induced by amino acid substitution at position 95 in rabies virus matrix protein. (2019)
  • Author(s): Isshu Kojima, Makoto Ozawa, Naoto Ito, Makoto Sugiyama, Tatsunori Masatani.
  • Organizer: The 18th Awaji International Forum on Infection and Immunity
  • Int'l Joint Research
• [Presentation] 狂犬病ウイルスM蛋白質95位のアミノ酸が関与するアポトーシス誘導機構の経時的解析 (2019)
  • Author(s): 児島一州、伊藤直人、杉山誠、小澤真、正谷達謄
  • Organizer: 第18回狂犬病研究会
• [Presentation] 狂犬病ウイルスM蛋白質95位のアミノ酸は後期アポトーシスにおける細胞膜破壊に関与する (2019)
  • Author(s): 児島一州、、伊藤直人、杉山誠、正谷達謄
  • Organizer: 第161回日本獣医学会学術集会
• [Presentation] P proteins from street rabies virus strains inhibit IKKε-mediated interferon signaling (2019)
  • Author(s): Masatani T
  • Organizer: The 10th Joint Symposium of Veterinary Research in East Asia
  • Int'l Joint Research / Invited
• [Presentation] Role of amino acid substitustion at position 95 in rabies virus matrix protein in cell membrane disruption (2019)
  • Author(s): Isshu Kojima, Naoto Ito, Makoto Sugiyama, Tatsunori Masatani
  • Organizer: 第66回日本ウイルス学会学術集会
• [Presentation] Rabies virus matrix protein is involved in formation of antiviral stress granules in infected cells (2017)
  • Author(s): Tatsunori Masatani, Koji Onomoto, Naoto Ito, Makoto Ozawa, Makoto Sugiyama, Mitsutoshi Yoneyama, Takashi Fujita
  • Organizer: 第65回日本ウイルス学会学術集会