Analysis of severe disease mechanism using mouse model infected with dengue virus, developing the symptoms of vascular leakage and bone marrow suppression.

• Project/Area Number: 17K08145
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Integrative animal science
• Research Institution: National 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)
• Project Period (FY): 2017-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: デング熱 / ガンマ・デルタＴ細胞 / サイトカインストーム / マウスモデル / IL-17 / ウイルス性出血熱 / RNAウイルス / デング出血熱 / デングウイルス / 好中球 / 血漿漏出 / IL-6 / 重症化 / 全身性感染症 / 多臓器不全 / 出血熱 / 感染動物モデル / 骨髄抑制 / ウイルス感染症 / ウィルス / 病理学 / 免疫学 / マイクロアレイ

Outline of Final Research Achievements

The aim of this study was to clarify the mechanism of severe disease using a novel mouse model of dengue virus infection developed independently. The study revealed that infection selectively proliferates gamma-delta T cells with IL-17A-producing Vγ4,6-type TCRs, and that the IL-17A produced acts in collaboration with TNF-α to overproduce cytokines, resulting in neutrophil proliferation and the production of effector molecules. The cause of the selective cell proliferation is not clear, but future elucidation of the mechanisms triggering IL-17A-producing gamma-delta T-cell proliferation will provide important insights into understanding the pathomechanisms of cytokine storm-induced pathology.

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Academic Significance and Societal Importance of the Research Achievements

デング熱は世界中の熱帯・亜熱帯地域に蔓延し、しばしば重症のデング出血熱を引き起こす。特異的な治療薬、普通の人に適応できるワクチンは開発されていない。重症化の原因は宿主の過剰な免疫反応によると考えられているが、その実態はあきらかではない。本研究では、独自に開発したマウスモデルを用いて、免疫反応が過剰に至るには液性因子であるIL-17Aを産生する特殊なガンマ・デルタT細胞が感染により選択的に活性化、増殖することによることを明らかにした。特定のガンマ・デルタT細胞が活性化される機序はまだ不明であるが、重症化機序解明、予防法開発につながる成果を得た。

Research Products

• [Journal Article] Chimeric flavivirus causes vascular leakage and bone marrow suppression in a mouse model (2023)
  • Author(s): Takeshi Kurosu, Keiko Hanabara, Azusa Asai, Sabar Pambudi, Supranee Phanthanawiboon, Magot Diata Omokoko, Yusuke Sakai, Tadaki Suzuki, Kazuyoshi Ikuta
  • Journal Title: Biochem Biophys Res Commun . Volume: 659 Pages: 54-61
  • DOI: 10.1016/j.bbrc.2023.04.003
  • Peer Reviewed
• [Journal Article] Chimeric flavivirus enables evaluation of antibodies against dengue virus envelope protein in vitro and in vivo. (2020)
  • Author(s): Kurosu T, Hanabara K, Asai A, Pambudi A, Phanthanawiboon A, Omokoko MD, Ono K, Saijo M, Ramasoota P, Ikuta K.
  • Journal Title: Scientific Report Volume: 10 Issue: 1 Pages: 21561-21561
  • DOI: 10.1038/s41598-020-78639-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Construction of a high-yield dengue virus by replacing nonstructural proteins 3-4B without increasing virulence (2018)
  • Author(s): Phanthanawiboon S, Pambudi S, Omokoko MD, Hanabara K, A-Nuegoonpipat A, Kamitani W, Ikuta K, Kurosu T
  • Journal Title: Biochem Biophys Res Commun. Volume: 495 Pages: 1221-1226
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Construction of a high-yield dengue virus by replacing nonstructural proteins 3?4B without increasing virulence (2018)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 致死性デング出血熱マウスモデルを用いたTNF-シグナル阻害による防御効果の分子機序解明 (2022)
  • Author(s): 黒須剛、奥崎大介、坂井祐介、Mohamad Al Kadi、下島昌幸、吉河智城、福士秀悦、永田典代、鈴木忠樹、海老原秀喜、西條政幸
  • Organizer: 第69回日本ウイルス学会学術集会
• [Presentation] Interleukin-17A released from intestinal γδT cells induces cytokine storm in mice with severe dengue (2022)
  • Author(s): Takeshi Kurosu, Daisuke Okuzaki, Yusuke Sakai, Mohamad Al Kadi, Supranee Phanthanawiboon, Yasusi Ami, Masayuki Shimojima, Tomoki Yoshikawa, Shuetsu Fukushi, Noriyo Nagata, Tadaki Suzuki, Daisuke Kamimura, Masaaki Murakami, Hideki Ebihara, Masayuki Saijo
  • Organizer: 第52回日本免疫学会学術集会
• [Presentation] Inflammation amplifier plays a critical role in severe dengue hemorrhagic fever (2019)
  • Author(s): Kurosu T, Okuzaki D, Shimojima M, Yoshikawa T, Phanthanawiboon S, Kamimura D, Murakami M, Saijo M
  • Organizer: Keystone Symposia Positive-strand RNA Viruses
  • Int'l Joint Research
• [Presentation] IL-17A produced from gamma/delta T cells plays a critical role in vascular leakage of severe dengue hemorrhagic fever in mice. (2019)
  • Author(s): Kurosu T, Phanathanawiboon S, Okuzaki D, Shimojima M, Yoshikawa T, Saijo M.
  • Organizer: 第６7回日本ウイルス学会学術集会
• [Presentation] デング熱重症化マウスモデルでは、γδT細胞から産生されたIL-17AがIL-6産生を増強し、血漿漏出を伴う致死的感染を引き起こしている。 (2019)
  • Author(s): 黒須剛、奥崎大介、Phanthanawiboon S、吉河智城、下島昌幸、村上正晃、上村大、永田典代、岩田奈織子、西條政幸
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] IL-17A produced from gamma/delta T cells plays a critical role in vascular leakage of severe dengue hemorrhagic fever in mice (2019)
  • Author(s): Kurosu T, Okuzaki D, Shimojima M, Yoshikawa T, Phanathanawiboon S, Kamimura D, Murakami M, Saijo M
  • Organizer: 第48回日本免疫学会学術集会
• [Presentation] マウスモデルを用いたデング出血熱重症化機序の解明 (2019)
  • Author(s): 黒須剛、奥崎大介、Supranee Phanthanawiboon、吉河智城、下島昌幸、西條政幸
  • Organizer: 第162回日本獣医学会学術集会
• [Presentation] Inflammation amplifier plays a critical role in severe dengue hemorrhagic fever (2018)
  • Author(s): Takeshi Kurosu, Daisuke Okuzaki, Masayuki Shimojima, Shuetsu Fukushi, Kamimura, Murakami, Tomoki Yoshikawa, Shunpei Watanabe, Supranee Phanathanawiboon, Masayuki Saijo
  • Organizer: 第６６回日本ウイルス学会学術集会
• [Presentation] Hematopathogenesis of chimeric dengue mouse model (2018)
  • Author(s): Supranee Phanthanawiboon, Takeshi Kurosu, Masayuki Shimojima, Shuetsu Fukushi, Tomoki Yoshikawa, Shumpei Watanabe, Tadaki Suzuki, Naoko Iwata-Yoshikawa, Noriyo Nagata, Masayuki Saijo
  • Organizer: 第６６回日本ウイルス学会学術集会
• [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
• [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
• [Presentation] The dynamics of disease progression in severe dengue. (2017)
  • Author(s): Takeshi Kurosu
  • Organizer: Joint International Tropical Medicine Meeting 2017
  • Int'l Joint Research / Invited