Innate immune responses induced by two coronavirus cell entry pathways

• Project/Area Number: 17K08868
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Virology
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: Matsuyama Shutoku 国立感染症研究所, ウイルス第三部, 室長 (90373399)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: コロナウイルス / 抗ウイルス薬 / 細胞侵入 / Furin / Coronavirus / infection / エンドソーム / 自然免疫 / プロテアーゼ

Outline of Final Research Achievements

In this study, we investigated the effect of coronavirus cell entry manner on subsequent virus growth. In addition to human coronavirus HCoV-229E, other human coronaviruses, HCoV-OC43 and HCoV-HKU1, were reported that their clinical isolates prefer the entry route using TMPRSS2 on the cell surface. This confirms our hypothesis that human coronaviruses evade the endosomal pathway in vivo. In addition, the identification of a cathepsin cleavage site in viral spike protein and generation of a mutant virus which only through endosomal pathway, to reveal the viral entry mechanism, were not yet successful.

Academic Significance and Societal Importance of the Research Achievements

コロナウイルスの細胞侵入経路、細胞の抗ウイルス効果発現、ウイルスRNAの複製、及びそれらの阻害剤を研究することは、現在アウトブレイクを起こしている新型コロナウイルスを理解する上で、役立つところは大きい。本研究によって既に得られていた知見により、既存薬「シクレソニド」を抗コロナウイルス薬として利用できることが見いだされていた。現在、新型コロナウイルスの治療薬として臨床の場で用いられ、後ろ向きコホート研究が行われている。

Research Products

• [Journal Article] The inhaled corticosteroid ciclesonide blocks coronavirus RNA replication by targeting viral NSP15 (2020)
  • Author(s): Shutoku Matsuyama, Miyuki Kawase, Naganori Nao, Kazuya Shirato, Makoto Ujike, Wataru Kamitani, Masayuki Shimojima, Shuetsu Fukushi
  • Journal Title: bioRxiv Volume: 03.11 Pages: 987016-987016
  • Open Access
• [Journal Article] Enhanced isolation of SARS-CoV-2 by TMPRSS2-expressing cells (2020)
  • Author(s): Matsuyama Shutoku、Nao Naganori、Shirato Kazuya、Kawase Miyuki、Saito Shinji、Takayama Ikuyo、Nagata Noriyo、Sekizuka Tsuyoshi、Katoh Hiroshi、Kato Fumihiro、Sakata Masafumi、Tahara Maino、Kutsuna Satoshi、Ohmagari Norio、Kuroda Makoto、Suzuki Tadaki、Kageyama Tsutomu、Takeda Makoto
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 117 Issue: 13 Pages: 7001-7003
  • DOI: 10.1073/pnas.2002589117
  • Peer Reviewed / Open Access
• [Journal Article] Biochemical Analysis of Coronavirus Spike Glycoprotein Conformational Intermediates during Membrane Fusion (2019)
  • Author(s): Kawase Miyuki、Kataoka Michiyo、Shirato Kazuya、Matsuyama Shutoku
  • Journal Title: Journal of Virology Volume: 93 Issue: 19 Pages: 00785-19
  • DOI: 10.1128/jvi.00785-19
  • Peer Reviewed
• [Journal Article] Middle East Respiratory Syndrome Coronavirus Spike Protein Is Not Activated Directly by Cellular Furin during Viral Entry into Target Cells (2018)
  • Author(s): Matsuyama Shutoku、Shirato Kazuya、Kawase Miyuki、Terada Yutaka、Kawachi Kengo、Fukushi Shuetsu、Kamitani Wataru
  • Journal Title: Journal of Virology Volume: 92 Issue: 19
  • DOI: 10.1128/jvi.00683-18
  • Peer Reviewed
• [Journal Article] Wild-type human coronaviruses prefer cell-surface TMPRSS2 to endosomal cathepsins for cell entry (2018)
  • Author(s): Shirato Kazuya、Kawase Miyuki、Matsuyama Shutoku
  • Journal Title: Virology Volume: 517 Pages: 9-15
  • DOI: 10.1016/j.virol.2017.11.012
  • Peer Reviewed