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The elucidation of pathogenic mechanisms of vascular leakage and bone marrow suppression in dengue virus mouse model

Research Project

Project/Area Number 15K14885
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeMulti-year Fund
Research Field Integrative animal science
Research InstitutionNational Institute of Infectious Diseases

Principal Investigator

KUROSU TAKESHI  国立感染症研究所, ウイルス第一部, 主任研究官 (70432432)

Research Collaborator OKUZAKI DAISUKE  大阪大学, 微生物病研究所, 助教 (00346131)
Project Period (FY) 2015-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Keywordsデング出血熱 / マウスモデル / 出血熱 / サイトカインストーム / 血症漏出 / フラビウイルス / 重症感染症 / デングウイルス / 感染病態 / 動物モデル / 重症化 / デング熱 / 感染モデル / 血漿漏出 / 感染
Outline of Final Research Achievements

Dengue hemorrhagic fever is characterized by thrombocytopenia and plasma leakage. We tried to elucidate the mechanism of severity, and elucidated the mechanism of pathogenesis using several kinds of dengue virus infection mouse models. As a result, in the following process occurs during the process of severity 1) abnormal activation of the macrophage. 2) Excessive production of inflammatory cytokines such as TNF-α. 3) Battling protection factors and exacerbating factors in vascular endothelial cells. 4) Multiple organ failure due to cytokine storm occurred at the end of the disease state, and factors involved in each step were identified. In the bone marrow, it was concluded that the erythrocyte - megakaryocyte precursor cell disorder has occurred. Furthermore, for the application of mouse model, the protective ability test of the therapeutic antibody was carried out and its effectiveness was shown.

Report

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

    (11 results)

All 2018 2017 2016 2015

All Journal Article (4 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 4 results,  Open Access: 4 results,  Acknowledgement Compliant: 3 results) Presentation (7 results) (of which Int'l Joint Research: 1 results,  Invited: 1 results)

  • [Journal Article] Construction of a high-yield dengue virus by replacing nonstructural proteins 3?4B without increasing virulence2018

    • Author(s)
      Phanthanawiboon Supranee、Pambudi Sabar、Omokoko Magot Diata、Hanabara Keiko、A-nuegoonpipat Atchareeya、Kamitani Wataru、Ikuta Kazuyoshi、Kurosu Takeshi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 495 Issue: 1 Pages: 1221-1226

    • DOI

      10.1016/j.bbrc.2017.11.137

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Sequence diversity of dengue virus type 2 in brain and thymus of infected interferon receptor KO mice: implications for dengue virulence.2016

    • Author(s)
      1.Dhole P, Nakayama EE, Saito A, Limkittikul K, Phanthanawiboon S, Shioda T, Kurosu T.
    • Journal Title

      Virology Journal

      Volume: 13 Issue: 1 Pages: 199-199

    • DOI

      10.1186/s12985-016-0658-4

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Acute Systemic Infection with Dengue Virus Leads to Vascular Leakage and Death through Tumor Necrosis Factor-α and Tie2/Angiopoietin Signaling in Mice Lacking Type I and II Interferon Receptors2016

    • Author(s)
      Supranee Phanthanawiboon, Kriengsak Limkittikul, Yusuke Sakai, Nobuyuki Takakura, Masayuki Saijo and Takeshi Kurosu
    • Journal Title

      PLOSOne

      Volume: 4 Issue: 2 Pages: e0148564-e0148564

    • DOI

      10.1371/journal.pone.0148564

    • Related Report
      2016 Research-status Report 2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Antibody with an engineered Fc region as a therapeutic agent against dengue virus infection.2015

    • Author(s)
      Ririn Ramadhany, Itaru Hirai, Tadahiro Sasaki, Ken-ichiro Ono, Pongrama Ramasoota, Kazuyoshi Ikuta, and Takeshi Kurosu
    • Journal Title

      Antiviral Research

      Volume: 124 Pages: 61-68

    • DOI

      10.1016/j.antiviral.2015.10.012

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Presentation] The dynamics of disease progression in severe dengue.2017

    • Author(s)
      Takeshi Kurosu, Daisuke Okuzaki, Kriengsak Limkittikul, Masayuki Shimojima, Shuetsu Fukushi, Shumpei Watanabe, Masayuki Saijo.
    • Organizer
      第58回日本熱帯医学会大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] The dynamics of disease progression in severe dengue.2017

    • Author(s)
      Takeshi Kurosu
    • Organizer
      Joint International Tropical Medicine Meeting 2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] The dynamics of disease progression in severe dengue.2017

    • Author(s)
      Takeshi Kurosu, Daisuke Okuzaki, Kriengsak Limkittikul, Masayuki Shimojima, Shuetsu Fukushi, Shumpei Watanabe, Masayuki Saijo.
    • Organizer
      第65回日本ウイルス学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Transcriptome analysis using a fatal mouse model for severe dengue.2016

    • Author(s)
      Kurosu T, Okuzaki D, Limkittikul K, Shimojima M, Fukushi S, Tani H, Saijo M
    • Organizer
      第64回日本ウイルス学会学術集会
    • Place of Presentation
      札幌
    • Year and Date
      2016-10-23
    • Related Report
      2016 Research-status Report
  • [Presentation] 2.Sequence Diversity of Dengue Virus Type 2 in Brain and Thymus of infected Interferon Receptor KO mice: Implications for Dengue Virulence.2016

    • Author(s)
      Dhole P, Nakayama EE, Limkittikul K, Phanthanawiboon S, Kazuyoshi I, Shioda T, Kurosu T.
    • Organizer
      第64回日本ウイルス学会学術集会
    • Place of Presentation
      札幌
    • Year and Date
      2016-10-23
    • Related Report
      2016 Research-status Report
  • [Presentation] Acute systemic infection with dengue virus leads vascular leakage and death through TNF-alpha and Tie2/Angiopoietin signaling in mice2015

    • Author(s)
      Takeshi Kurosu, Supranee Phanthanawiboon, Yusuke Sakai, Kriengsak Limkittikul, Masayuki Saijo
    • Organizer
      第63回日本ウイルス学会
    • Place of Presentation
      福岡
    • Year and Date
      2015-11-22
    • Related Report
      2015 Research-status Report
  • [Presentation] デングウイルス感染マウスモデルを用いた重症化機序の解析2015

    • Author(s)
      黒須 剛、Supranee Phanthanawiboon、坂井祐介、Kriengsak Limkittikul
    • Organizer
      第158回日本獣医学会
    • Place of Presentation
      十和田
    • Year and Date
      2015-09-07
    • Related Report
      2015 Research-status Report

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Published: 2015-04-16   Modified: 2020-03-17  

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