The mechanisms of asthma exacerbation induced by viral infection and the development of strategy for controlling the pathogenesis(Fostering Joint International Research)

• Project/Area Number: 15KK0321
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research)
• Allocation Type: Multi-year Fund
• Research Field: Respiratory organ internal medicine
• Research Institution: Tokyo Women's Medical University
• Principal Investigator: Ashino Shigeru 東京女子医科大学, 医学部, 講師 (10507221)
• Project Period (FY): 2016 – 2019
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥12,220,000 (Direct Cost: ¥9,400,000、Indirect Cost: ¥2,820,000)
• Keywords: 気管支喘息 / ウイルス感染 / 重症気管支喘息 / アレルギー・ぜんそく / ウィルス感染 / 呼吸器疾患 / 重症喘息 / アレルギー

Outline of Final Research Achievements

Viral infection is a risk factor for asthma exacerbation, but the underlying mechanisms are not fully determined. In particular it is not clear how viral components are involved in asthma exacerbation. Therefore, we investigated the mechanisms and pathogenesis using our mouse models.
In this study, the viral infection-asthma models were established by allergen sensitization and challenge followed by viral components (single-stranded RNA (ssRNA) and double-stranded RNA (dsRNA)) or respiratory syncytial virus (RSV) administration, which can mimic human severe asthma.
It was found that allergen-induced asthma was more severely exacerbated in mice administered dsRNA than ssRNA, which stimulated toll-like receptor 3 (TLR3) and TLR7 respectively. In addition, RSV induced asthma exacerbation, but the pathogenesis was attenuated in knock-out mice of TLR3 but not TLR7. Targeting TLR3 may be a potential therapeutic target to control asthma exacerbation by an infection of virus such as RSV.

Academic Significance and Societal Importance of the Research Achievements

風邪症候群を引き起こすウイルスに感染した喘息患者の病態が、著しく増悪する症例は全体の約70%であることが知られており、重症患者群の一部では難治化することが報告されている。現在、ウイルス感染による喘息悪化のメカニズムは完全に解明されておらず、治療法の確立も十分でないために、本研究で得られた新規知見は有効な制御法を開発していく上で重要な成果になると考えている。特に、ウイルス成分に着目して治療ターゲットを絞り込むことで、より効果的な治療戦略を創出でき、本研究によってその研究基盤を構築できていると考えている。

Research Products

• [Int'l Joint Research] National Jewish Health(米国) (2018)
  • Year and Date: 2018-01-29
• [Journal Article] Effect of Cholecalciferol in Food Allergy Mouse Model Is Associated with Decrease of CD69⁺ CD4⁺ T Cells (2019)
  • Author(s): Zaim E, Ashino S, Osaka T, Yanagisawa N, Yagi J
  • Journal Title: Journal of Nutritional Science and Vitaminology Volume: 65 Issue: 2 Pages: 113-122
  • DOI: 10.3177/jnsv.65.113
  • NAID: 130007639843
  • ISSN: 0301-4800, 1881-7742
  • Year and Date: 2019-04-30
  • Peer Reviewed / Open Access
• [Presentation] Double But Not Single-Stranded RNA Exacerbates Allergen-Induced Airway Hyperresponsiveness and Airway Inflammation (2020)
  • Author(s): Shigeru Ashino, Katsuyuki Takeda, Hidemitsu Kitamura, Atsushi Kurokawa, Tomohiro Akaba, Mitsuko Kondo, Kiyoshi Takeyama, Etsuko Tagaya, Naoko Yanagisawa, and Erwin W. Gelfand
  • Organizer: American Academy of Allergy Asthma and Immunology (新型コロナウイルス感染拡大のためabstractのみ公表)
  • Int'l Joint Research
• [Presentation] The Crucial Roles of Neurokinin A and Neurokinin Receptor 2 Signaling in Asthma Exacerbation Induced by a Viral Component, Double-Stranded RNA. (2018)
  • Author(s): Shigeru Ashino, Hidemitsu Kitamura, Tomohiro Akaba, Kiyoshi Takeyama, Jun Tamaoki, and Junji Yagi.
  • Organizer: 第67回日本アレルギー学会学術大会
• [Presentation] The Effects of Viral Components, Single-Stranded RNA and Double-Stranded RNA, on Allergen-Induced Airway Hyperresponsiveness and Airway Inflammation. (2018)
  • Author(s): Shigeru Ashino, Hidemitsu Kitamura, Tomohiro Akaba, Kiyoshi Takeyama, Jun Tamaoki, and Junji Yagi.
  • Organizer: American Thoracic Society International Conference 2018.
  • Int'l Joint Research