Development of novel therapeutics against emerging infectious diseases by targeting blood–brain barrier

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K19394
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 47:Pharmaceutical sciences and related fields
• Research Institution: National Institute of Health Sciences
• Principal Investigator: Kanda Yasunari 国立医薬品食品衛生研究所, 薬理部, 部長 (70510387)
• Co-Investigator(Kenkyū-buntansha): 坡下 真大 名古屋市立大学, 医薬学総合研究院(薬学), 講師 (20613384)
• Project Period (FY): 2022-06-30 – 2024-03-31
• Keywords: iPS細胞 / COVID-19 / SARS-CoV-2 / 脳毛細血管内皮細胞 / 血液脳関門 / Wnt / 後遺症 / バリアー機能

Outline of Final Research Achievements

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) is associated with various neurological symptoms. Here we investigated the effect of SARS-CoV-2 on the CNS. We found that iPSC-derived brain microvascular endothelial like cells (iPSC-BMELCs) were infected with SARS-CoV-2 via its ACE2 receptor. SARS-CoV-2 infection resulted in decrease in TEER and induction of several proinflammatory genes, which are known to be elevated in patients with COVID-19. Furthermore, RNA-seq analysis revealed that SARS-CoV-2 targeted canonical pathway of Wnt signaling in iPSC-BMELCs. The Wnt activator partially inhibited the infection and the subsequent inflammatory responses. These findings suggest that SARS-CoV-2 infection causes BBB dysfunction via Wnt signaling. Thus, iPSC-BMELCs are a useful in vitro model for elucidating COVID-19 neuropathology and drug development.

Free Research Field

レギュラトリーサイエンス

Academic Significance and Societal Importance of the Research Achievements

COVID-19重症化時に様々な神経症状を引き起こすことが知られており、long COVID-19と呼ばれるような長期症状が懸念されている。本研究において、血液脳関門の構成細胞である脳毛細血管内皮細胞を用いてSARS-CoV-2感染メカニズムを明らかにすることができることを明らかにした。これによりCOVID-19の病態メカニズムを解明し、long COVID-19の克服に向けて新たな治療薬や診断マーカーなどの開発につながることが期待できる。