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Prion protein signaling induces M2 macrophage polarization and protects from lethal influenza infection in mice

Research Project

Project/Area Number 19K08930
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 InstitutionThe University of Tokushima

Principal Investigator

CHIDA Junji  徳島大学, 先端酵素学研究所, 助教 (20437651)

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: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywordsインフルエンザ / プリオン蛋白質 / 抗プリオン抗体 / 脳症 / 多臓器不全 / 重症化 / 抗PrP抗体 / SFK蛋白質 / マクロファージ / SFKタンパク質 / 炎症性サイトカイン / Src / Src蛋白質
Outline of Research at the Start

・Srcのリン酸化が起こる浸潤性細胞を特定する。
申請者らは、抗PrP抗体を前投与したIAV感染マウスの肺において、何らかの浸潤性細胞でSrcタンパク質のリン酸化が起こることを見出した。この浸潤性細胞は抗PrP抗体を投与したIAV非感染肺では認められないことから、自然免疫系を担当する細胞である可能性が高い。それがマクロファージ、樹状細胞、好中球であるのかそれ以外の細胞なのかを明らかにする。
・抗PrP抗体の投与が、如何にしてIAV重症化を軽減するのかその機序を明確にする。
・PrPを分子標的とした治療が可能であるのか否かについて検証する。

Outline of Final Research Achievements

We show here that stimulation of PrPC with anti-PrP mAbs protected mice from lethal infection with IAVs by stimulating macrophage polarization to an anti-inflammatory M2 phenotype through activation of SFKs in infected lungs. IAVs are causative agents for seasonal epidemic outbreaks of influenza, and often cause high morbidity and mortality in infected people, particularly in the young and elderly and those with underlying chronic diseases. The other problem with IAV infections is that new IAV strains, which are resistant to currently available anti-influenza agents such as neuraminidase inhibitors, have been emerging in human populations. Our current results showing that targeting PrPC with anti-PrP mAbs protected against lethal infection with IAVs in mice give rise to the possibility that PrPC-targeting therapeutics might be beneficial in influenza infection.

Academic Significance and Societal Importance of the Research Achievements

インフルエンザの重症化機序が明確でない現状で、抗ウイルス薬の一方的な投与が原因で、抗ウイルス薬の耐性株が世界各地で急増している。一方、ワクチンではインフルエンザの感染予防は不可能であると世界保健機関が既に提言している。このような背景から、抗ウイルス薬とは作用機序の異なる「耐性株を出現させない治療薬」の開発が急務であるが、これまで宿主因子を標的とした治療薬の開発は国内外で成功例がない。従って、宿主因子であるPrPを分子標的とした治療薬を開発する試みはこれまでに例がなく、本研究の成果は、今後この方面の研究に大きく貢献することが期待される。

Report

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

    (11 results)

All 2022 2021 2020 2019

All Journal Article (7 results) (of which Peer Reviewed: 7 results,  Open Access: 7 results) Presentation (3 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Electrochemical enzyme-based blood ATP and lactate sensor for a rapid and straightforward evaluation of illness severity2022

    • Author(s)
      Nishiyama Keine、Mizukami Ryohei、Kuki Shizuka、Ishida Akihiko、Chida Junji、Kido Hiroshi、Maeki Masatoshi、Tani Hirofumi、Tokeshi Manabu
    • Journal Title

      Biosensors and Bioelectronics

      Volume: 198 Pages: 113832-113832

    • DOI

      10.1016/j.bios.2021.113832

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Ethanolamine Is a New Anti-Prion Compound2021

    • Author(s)
      Uchiyama Keiji、Hara Hideyuki、Chida Junji、Pasiana Agriani Dini、Imamura Morikazu、Mori Tsuyoshi、Takatsuki Hanae、Atarashi Ryuichiro、Sakaguchi Suehiro
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 22 Issue: 21 Pages: 11742-11742

    • DOI

      10.3390/ijms222111742

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Neurotropic influenza A virus infection causes prion protein misfolding into infectious prions in neuroblastoma cells2021

    • Author(s)
      Hara Hideyuki、Chida Junji、Uchiyama Keiji、Pasiana Agriani Dini、Takahashi Etsuhisa、Kido Hiroshi、Sakaguchi Suehiro
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1 Pages: 10109-10109

    • DOI

      10.1038/s41598-021-89586-6

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Vaporized Hydrogen Peroxide and Ozone Gas Synergistically Reduce Prion Infectivity on Stainless Steel Wire2021

    • Author(s)
      Hara Hideyuki、Chida Junji、Pasiana Agriani Dini、Uchiyama Keiji、Kikuchi Yutaka、Naito Tomoko、Takahashi Yuichi、Yamamura Junji、Kuromatsu Hisashi、Sakaguchi Suehiro
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 22 Issue: 6 Pages: 3268-3268

    • DOI

      10.3390/ijms22063268

    • NAID

      120007164927

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Prion Protein is a Novel Modulator of Influenza: Potential Implications for Anti-Influenza Therapeutics2020

    • Author(s)
      Sakaguchi Suehiro、Chida Junji
    • Journal Title

      Current Issues in Molecular Biology

      Volume: 37 Pages: 21-32

    • DOI

      10.21775/cimb.037.021

    • NAID

      120006979198

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Prion protein signaling induces M2 macrophage polarization and protects from lethal influenza infection in mice2020

    • Author(s)
      Chida Junji、Hara Hideyuki、Uchiyama Keiji、Takahashi Etsuhisa、Miyata Hironori、Kosako Hidetaka、Tomioka Yukiko、Ito Toshihiro、Horiuchi Hiroyuki、Matsuda Haruo、Kido Hiroshi、Sakaguchi Suehiro
    • Journal Title

      PLOS Pathogens

      Volume: 16 Issue: 8 Pages: e1008823-e1008823

    • DOI

      10.1371/journal.ppat.1008823

    • NAID

      120006956844

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Strain-Dependent Prion Infection in Mice Expressing Prion Protein with Deletion of Central Residues 91?1062020

    • Author(s)
      Uchiyama Keiji、Miyata Hironori、Yamaguchi Yoshitaka、Imamura Morikazu、Okazaki Mariya、Pasiana Agriani Dini、Chida Junji、Hara Hideyuki、Atarashi Ryuichiro、Watanabe Hitomi、Kondoh Gen、Sakaguchi Suehiro
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 21 Issue: 19 Pages: 7260-7260

    • DOI

      10.3390/ijms21197260

    • NAID

      120006959718

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] インフルエンザウイルス感染は神経細胞において感染性プリオン産生を引き起こす.2021

    • Author(s)
      原 英之, 千田 淳司, 坂口 末廣.
    • Organizer
      第44回日本分子生物学会年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Prion protein protects mice from lethal influenza with influenza A virus.2019

    • Author(s)
      千田 淳司, 原 英之, 坂口 末廣.
    • Organizer
      第42回日本分子生物学会大会
    • Related Report
      2019 Research-status Report
  • [Presentation] Elucidation of pathogenic mechanism in prion disease using virus infection.2019

    • Author(s)
      原 英之, 千田 淳司, 坂口 末廣.
    • Organizer
      第42回日本分子生物学会大会
    • Related Report
      2019 Research-status Report
  • [Patent(Industrial Property Rights)] 非アルコール性脂肪肝炎を治療または予防するための医薬組成物2022

    • Inventor(s)
      坂口 末廣, 千田 淳司
    • Industrial Property Rights Holder
      国立大学法人徳島大学
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2022-008773
    • Filing Date
      2022
    • Related Report
      2021 Annual Research Report

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

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