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Study of the parainfluenza virus interferon antagonism as a basis for attenuated recombinant virus vaccines

Research Project

Project/Area Number 19K08928
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54030:Infectious disease medicine-related
Research InstitutionShiga University of Medical Science

Principal Investigator

Gotoh Bin  滋賀医科大学, 医学部, 非常勤講師 (00211920)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywordsパラインフルエンザウイルス1型 / パラインフルエンザウイルス3型 / Cタンパク質 / インターフェロン / JAK1 / TYK2 / IFNAR2 / レスピロウイルス / Cタンパク質 / パラインフルエンザウイルス / ワクチン
Outline of Research at the Start

パラインフルエンザウイルス(PIV)のアクセサリー蛋白質Cは、抗インターフェロン(IFN)能を含む多彩な機能をもち、ウイルスの増殖をサポートする。C蛋白質を発現しない組換えウイルスは弱毒化し生ワクチンの有力な候補となるが、抗IFN能以外の増殖に関わる重要な機能まで喪失するため、十分な量のウイルスを得ることは難しい。そこで本研究では、先ずⅠ型PIV(PIV1)、3型PIV(PIV3) C蛋白質の抗IFN機構の全容を解明し、次に、その情報をもとに、抗IFN能のみを欠失したC変異体を発現する組換えPIVをデザインし、それがワクチンの基準を満たすかどうかを検討する。

Outline of Final Research Achievements

We analyzed the mechanism by which the C proteins of respiroviruses, including parainfluenza viruses type 1 and type 3, inhibit type I interferon (IFN)-mediated anti-viral responses. The respirovirus C proteins were found to suppress activation of the IFN receptor-associated kinases, JAK1 and TYK2, and thereby inhibit IFN responses. The C proteins seem to target unknown molecules except for STAT1, JAK1, and IFNAR2. The C deletion mutant, which lacks the binding capacity for IFNAR2, regained its binding capacity by a single point mutation. Therefore attenuated recombinant virus vaccine lacking the IFN antagonism might easily revert to virulence.

Academic Significance and Societal Importance of the Research Achievements

3型パラインフルエンザウイルス(PIV3)は、ときに重症細気管支炎・肺炎を乳幼児に引き起こす。また、1型PIV(PIV1)はクループの原因となり、気管切開や挿管が必要となるほど重症化することがある。これらの感染症に特異的な治療法はなく、有効なワクチンの開発が望まれる。PIV1やPIV3は、宿主が産生するインターフェロン(IFN)の抗ウイルス作用から回避する機構を備えている。本研究では1型3型に共通する回避機構を明らかにした。また、抗IFN能を喪失した組換えウイルスワクチンを作成する場合、毒性復帰しやすい可能性があり、その点で十分な注意が必要であることを示した。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (9 results)

All 2021 2019 Other

All Journal Article (3 results) (of which Peer Reviewed: 3 results,  Open Access: 2 results) Presentation (4 results) Remarks (2 results)

  • [Journal Article] M protein of subacute sclerosing panencephalitis virus, synergistically with the F protein, plays a crucial role in viral neuropathogenicity2021

    • Author(s)
      Satoh Yuto、Higuchi Kurara、Nishikawa Daichi、Wakimoto Hiroshi、Konami Miho、Sakamoto Kento、Kitagawa Yoshinori、Gotoh Bin、Jiang Da-Peng、Hotta Hak、Itoh Masae
    • Journal Title

      Journal of General Virology

      Volume: 102 Issue: 10 Pages: 001682-001682

    • DOI

      10.1099/jgv.0.001682

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Neutralizing antibody-dependent and -independent immune responses against SARS-CoV-2 in cynomolgus macaques2021

    • Author(s)
      Ishigaki Hirohito、Nakayama Misako、Kitagawa Yoshinori、Nguyen Cong Thanh、Hayashi Kaori、Shiohara Masanori、Gotoh Bin、Itoh Yasushi
    • Journal Title

      Virology

      Volume: 554 Pages: 97-105

    • DOI

      10.1016/j.virol.2020.12.013

    • NAID

      120006953803

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Respirovirus C protein inhibits activation of type I interferon receptor‐associated kinases to block JAK‐STAT signaling2019

    • Author(s)
      Kitagawa Yoshinori、Yamaguchi Mayu、Kohno Miki、Sakai Madoka、Itoh Masae、Gotoh Bin
    • Journal Title

      FEBS Letters

      Volume: 594 Issue: 5 Pages: 864-877

    • DOI

      10.1002/1873-3468.13670

    • NAID

      120006776241

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Presentation] Middle East Respiratory Syndrome coronavirus ORF4b protein inhibits type I IFN signaling pathway though inhibition of STAT1/2 phosphorylation2021

    • Author(s)
      北川善紀、野中梨聖、高澤博人、伊藤正恵、後藤敏
    • Organizer
      第68回日本ウイルス学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Role of the measles virus L protein in the development of subacute sclerosing panencephalitis2021

    • Author(s)
      坂本賢人、小浪海峰、樋口遙、姜大鵬、脇本浩史、亀田森羅、佐藤友人、北川善紀、後藤敏、高橋健一、堀田博、伊藤正恵
    • Organizer
      第68回日本ウイルス学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Middle East respiratory syndrome coronavirus ORF4b inhibits IKKα-mediated phosphorylation of IRF7 involved in activation of the alpha interferon gene2019

    • Author(s)
      Yoshinori Kitagawa, Masae Itoh, Bin Gotoh,
    • Organizer
      Th 67th Annual Meeting of the Japanese Society for Virology
    • Related Report
      2019 Research-status Report
  • [Presentation] Characterization of the mutations in the L protein of the Kobe-1 strain of a subacute sclerosing panencephalitis (SSPE) virus2019

    • Author(s)
      Yuto Satoh, Miho Konami, Hiroshi Wakimoto, Kurara Higuchi, Da-Peng Jiang, Kento Sakamoto, Yoshinori Kitagawa, Bin Gotoh, Ken-ichi Takahashi, Hak Hotta, Masae Itoh.
    • Organizer
      Th 67th Annual Meeting of the Japanese Society for Virology
    • Related Report
      2019 Research-status Report
  • [Remarks] 滋賀医科大学病理学講座微生物感染症学部門

    • URL

      http://www.shiga-med.ac.jp/-hqmicro/

    • Related Report
      2021 Annual Research Report
  • [Remarks] 滋賀医科大学病理学講座微生物感染症学部門

    • URL

      http://www.shiga-med.ac.jp/~hqmicro/

    • Related Report
      2020 Research-status Report 2019 Research-status Report

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Published: 2019-04-18   Modified: 2023-01-30  

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