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Progressive multifocal leukoencephalopathy: Dynamics of PML-NBs of JC virus-infected glial cells

Research Project

Project/Area Number 15K06759
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Nerve anatomy/Neuropathology
Research InstitutionTokyo Medical University

Principal Investigator

Hara Yukiko  東京医科大学, 医学部, 准教授 (40313267)

Co-Investigator(Kenkyū-buntansha) 菅間 博  杏林大学, 医学部, 教授 (10195191)
矢澤 卓也  獨協医科大学, 医学部, 教授 (50251054)
千葉 知宏  杏林大学, 医学部, 講師 (60398617)
矢澤 華子 (佐藤 / 佐藤 華子)  獨協医科大学, 医学部, 講師 (60438132)
石井 順  獨協医科大学, 医学部, 助教 (80749599)
Project Period (FY) 2015-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2017: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2015: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
Keywords進行性多巣性白質脳症 / JC virus / PML-NBs / 脱髄 / 細胞周期 / 転写因子 / 細胞変性 / JCウイルス / PML-NBs / 腫瘍抑制 / agnoprotein
Outline of Final Research Achievements

Progressive multi focal leukoencephalopathy (PML) is a demyelinating disorder caused due to JCV infection. Previous studies demonstrated that JCV capsid proteins accumulate to the promyelocytic leukemia nuclear bodies (PML-NBs), where they are assembled into virions. To clarify functions of PML-NBs, we expressed JCV capsid proteins, VP1 and VP2/VP3 in the presence or absence of agnoprotein, and assembly of virus-like particles (VLPs) was examined. The results indicated that (1) JCV efficiently produces VLPs, in the presence of agnoprotein, with regulated expression levels of capsid proteins. (2) Overexpression of the capsid proteins, in the absence of agnoprotein, results in ectopic assembly of irregular VLPs. (3) Moreover, mRNA expression levels of transcription factors increased in presence of agnoprotein. Thus, it may be indicated that the levels of transcription factors, which are important for JCV reproduction would be increased, when capsid assembly occurs at PML-NBs.

Academic Significance and Societal Importance of the Research Achievements

PML-NBsは広く真核細胞の核内にみられる構造であるが、その機能は多彩である。ウイルス感染においてはウイルス遺伝子の転写や、ウイルス粒子形成の場として研究されているが、JCV感染でPML-NBsの解析を積極的に行っている研究は、世界的に少数である。希少研究である上に、培養細胞と人体組織を関連させたtranslational researchが行われているという点で、本研究は学術的意義が高い。また、近年、免疫抑制剤などの使用に伴うJCV再活性化、PML発症が問題となっている。JCV溶解感染のメカニズムを明らかにすれば、将来的には薬剤関連PMLの対策にも貢献できる可能性がある。

Report

(5 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • 2015 Research-status Report
  • Research Products

    (14 results)

All 2019 2018 2017 2016 2015

All Journal Article (10 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 9 results,  Open Access: 6 results,  Acknowledgement Compliant: 2 results) Presentation (4 results) (of which Invited: 3 results)

  • [Journal Article] A controlled inflammation and a regulatory immune system are associated with more favorable prognosis of progressive multifocal leukoencephalopathy.2019

    • Author(s)
      Sanjo N, Nose Y, Shishido-Hara Y, Mizutani S, Sekijima Y, Aizawa H, Tanizawa T, Yokota T.
    • Journal Title

      J Neurol.

      Volume: 266 Issue: 2 Pages: 369-377

    • DOI

      10.1007/s00415-018-9140-0

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] A Punctate Magnetic Resonance Imaging Pattern in a Patient with Systemic Lupus Erythematosus Is an Early Sign of Progressive Multifocal Leukoencephalopathy: A Clinicopathological Study2018

    • Author(s)
      Ishii J, Shishido-Hara Y, Kawamoto M, Fujiwara S, Imai Y, Nakamichi K, Kohara N
    • Journal Title

      Internal Medicine

      Volume: 57 Issue: 18 Pages: 2727-2734

    • DOI

      10.2169/internalmedicine.0696-17

    • NAID

      130007484368

    • ISSN
      0918-2918, 1349-7235
    • Year and Date
      2018-09-15
    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Two patients with progressive multifocal leukoencephalopathy with immune response against JC virus showing good long-term outcome by combination therapy of mefloquine, mirtazapine, and risperidone2018

    • Author(s)
      赤川 優美、上野 晃弘、池田 淳司、石井 亘、宍戸-原 由紀子、関島 良樹
    • Journal Title

      Rinsho Shinkeigaku

      Volume: 58 Issue: 5 Pages: 324-331

    • DOI

      10.5692/clinicalneurol.cn-001166

    • NAID

      130006744292

    • ISSN
      0009-918X, 1882-0654
    • Related Report
      2018 Annual Research Report 2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Pathologic Findings and Clinical Course of Midline Paraventricular Gliomas Diagnosed Using a Neuroendoscope2018

    • Author(s)
      Fukami Shinjiro、Nakajima Nobuyuki、Okada Hirofumi、Akimoto Jiro、Miki Tamotsu、Fukuhara Hirokazu、Shishido-Hara Yukiko、Nagao Toshitaka、Tsuda Masumi、Kohno Michihiro
    • Journal Title

      World Neurosurgery

      Volume: - Pages: e366-e377

    • DOI

      10.1016/j.wneu.2018.02.185

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Prognostic factors for primary central nervous system lymphomas treated with high-dose methotrexate-based chemo-radiotherapy2017

    • Author(s)
      Lee Jeunghun、Shishido-Hara Yukiko、Suzuki Kaori、Shimizu Saki、Kobayashi Keiichi、Kamma Hiroshi、Shiokawa Yoshiaki、Nagane Motoo
    • Journal Title

      Japanese Journal of Clinical Oncology

      Volume: 47 Issue: 10 Pages: 925-934

    • DOI

      10.1093/jjco/hyx098

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Fingolimod-associated PML with mild IRIS in MS2017

    • Author(s)
      Nishiyama Shuhei、Misu Tatsuro、Shishido-Hara Yukiko、Nakamichi Kazuo、Saijo Masayuki、Takai Yoshiki、Takei Kentarou、Yamamoto Naoki、Kuroda Hiroshi、Saito Ryuta、Watanabe Mika、Tominaga Teiji、Nakashima Ichiro、Fujihara Kazuo、Aoki Masashi
    • Journal Title

      Neurology - Neuroimmunology Neuroinflammation

      Volume: 5 Issue: 1

    • DOI

      10.1212/nxi.0000000000000415

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Progressive Multifocal Leukoencephalopathy with Inflammatory Reactions2016

    • Author(s)
      宍戸-原 由紀子、内原俊記、三條伸夫
    • Journal Title

      BRAIN and NERVE

      Volume: 68 Issue: 4 Pages: 479-488

    • DOI

      10.11477/mf.1416200422

    • ISSN
      1344-8129, 1881-6096
    • Year and Date
      2016-04-01
    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Progressive Multifocal Leukoencephalopathy with Balanced CD4/CD8 T-Cell Infiltration and Good Response to Mefloquine Treatment2016

    • Author(s)
      Sanjo N, Kina S, Shishido-Hara Y, Nose Y, Ishibashi S, Fukuda T, Maehara K, Eishi Y, Mizusawa H, Yokota T
    • Journal Title

      Internal Medicine

      Volume: 55 Issue: 12 Pages: 1631-1635

    • DOI

      10.2169/internalmedicine.55.6051

    • NAID

      130005157669

    • ISSN
      0918-2918, 1349-7235
    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 進行性多巣性白質農相の病理 -JCウイルス増殖と宿主免疫応答のバランスを考える-2016

    • Author(s)
      宍戸-原 由紀子
    • Journal Title

      神経内科

      Volume: 84 Pages: 305-311

    • Related Report
      2015 Research-status Report
  • [Journal Article] Progressive Multifocal Leukoencephalopathy -Dot-shaped inclusions and virus-host interactions-2015

    • Author(s)
      Shishido-Hara Y
    • Journal Title

      Neuropathology

      Volume: 35 Issue: 5 Pages: 487-496

    • DOI

      10.1111/neup.12203

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] シンポジウム9 中枢神経 ナタリツマブPML 進行性多巣性白質脳症の病理:宿主免疫レベルと病理所見の多様性2017

    • Author(s)
      宍戸-原 由紀子
    • Organizer
      第36回日本画像医学会
    • Place of Presentation
      東京
    • Year and Date
      2017-02-25
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] 進行性多巣性白質脳症における最近のトピックス2017

    • Author(s)
      宍戸-原 由紀子
    • Organizer
      多発性硬化症研究会
    • Place of Presentation
      松本
    • Year and Date
      2017-02-21
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] シンポジウム1 進行性多巣性白質脳症の診断・治療の新展開: 進行性多巣性白質脳症の分子病態と病理2016

    • Author(s)
      宍戸-原 由紀子
    • Organizer
      第21回日本神経感染症学会総会・学術大会
    • Place of Presentation
      金沢
    • Year and Date
      2016-10-21
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] JC viral inclusions in progressive multifocal leukoencephalopathy: Scaffolding promyelocytic leukemia nuclear bodies (PML-NBs) grow with cell cycle transition through S-to-G2-like state in the enlarging nuclei of oligodendrocytes2015

    • Author(s)
      Shishido-Hara Y
    • Organizer
      2nd International Conference on PML
    • Place of Presentation
      Merundel, Sweden
    • Year and Date
      2015-08-25
    • Related Report
      2015 Research-status Report

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Published: 2015-04-16   Modified: 2020-03-30  

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