Sttudy of host proteases that activate influenza viruses in vivo

• Project/Area Number: 26293105
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Virology
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: Takeda Makoto 国立感染症研究所, ウイルス第三部, 部長 (40311401)
• Co-Investigator(Renkei-kenkyūsha): SAKAI Kouji 国立感染症研究所, ウイルス第三部, 主任研究官 (70515535)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥15,990,000 (Direct Cost: ¥12,300,000、Indirect Cost: ¥3,690,000); Fiscal Year 2016: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2015: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2014: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
• Keywords: プロテアーゼ / インフルエンザウイルス / パラミクソウイルス / センダイウイルス / 開裂 / パラインフルエンザウイルス / ウィルス / ウイルス / TMPRSS2

Outline of Final Research Achievements

Using knockout (KO) mice we have previously revealed that TMPRSS2, which is expressed on epithelia of the respiratory tract is an essential protease for proteolytic activation of influenza viruses. In TMPRSS2 KO mice the hemagglutinin (HA) of influenza viruses remained to be uncleared and virus replication was severely impaired. In the present study we focused on Sendai virus, a member of the Paramyxoviridae family, because mice are the natural host of Sendai virus and Sendai virus also requires host proteases for its activation in vivo. Sendai virus showed a lethal infection for wild type mice, while TMPRSS2 KO mice were resistant to the Sendai virus infection. The replication of Sendai virus was severely restricted in the TMPRSS2 KO mice. These data for the first time demonstrated that TMPRSS2 is the essential protease for proteolytic activation of an ARI virus, Sendai virus, in the natural host.

Research Products

• [Journal Article] A Mutant H3N2 Influenza Virus Uses an Alternative Activation Mechanism in TMPRSS2 Knockout Mice by Loss of an Oligosaccharide in the Hemagglutinin Stalk Region (2015)
  • Author(s): Sakai K, Sekizuka T, Ami Y, Nakajima N, Kitazawa M, Sato Y, Nakajima K, Anraku M, Kubota T, Komase K, Takehara K, Hasegawa H, Odagiri T, Tashiro M, Kuroda M, Takeda M
  • Journal Title: J Virol Volume: 89 Issue: 9 Pages: 5154-5158
  • DOI: 10.1128/jvi.00124-15
  • Peer Reviewed / Open Access
• [Journal Article] The Host Protease TMPRSS2 Plays a Major Role in In Vivo Replication of Emerging H7N9 and Seasonal Influenza Viruses (2014)
  • Author(s): Sakai K, Ami Y, Tahara M, Kubota T, Anraku M, Abe M, Nakajima N, Sekizuka T, Shirato K, Suzaki Y, Ainai A, Nakatsu Y, Kanou K, Nakamura K, Suzuki T, Komase K, Nobusawa E, Maenaka K, Kuroda M, Hasegawa H et al
  • Journal Title: J Virol Volume: 88 Issue: 10 Pages: 5608-5616
  • DOI: 10.1128/jvi.03677-13
  • Peer Reviewed / Open Access
• [Presentation] 呼吸病ウイルスの病原性発現に関わる宿主プロテアーゼTMPRSS2の意義 (2016)
  • Author(s): 酒井宏治、中島典子、駒瀬勝啓、竹田誠
  • Organizer: 第57回日本臨床ウイルス学会
  • Place of Presentation: 郡山
  • Year and Date: 2016-06-18
• [Presentation] A natural host model revealed the essential role of the host protease TMPRSS2 for respiratory paramyxovirus pathogenicity. (2015)
  • Author(s): Takeda M, Sakai K, Ami Y, Kitazawa M, Nakajima K, Natthanan S, Anraku M, Nakajima N, Komase K, Takehara K, Hasegawa H, Tashiro M.
  • Organizer: 第63回日本ウイルス学会
  • Place of Presentation: 福岡
  • Year and Date: 2015-11-22
• [Presentation] Host and viral determinants of proteolytic activation of influenza viruses (2015)
  • Author(s): Sakai K, Ami Y, Kitazawa M, Nakajima K, Sekizuka T, Nakajima N, Anraku M, Tahara M, Kubota T, Komase K, Takehara K, Odagiri T, Kuroda M, Hasegawa H, Kawaoka Y, Tashiro M, Takeda M
  • Organizer: 第16回マイナス鎖RNAウイルス国際会議
  • Place of Presentation: イタリア、シエナ市
  • Year and Date: 2015-06-14
  • Int'l Joint Research
• [Presentation] The host protease TMPRSS2 is essential for influenza A virus pathogenicity. (2014)
  • Author(s): 95.Sakai K, Ami Y, Tahara M, Kubota T, Anraku M, Nakajima N, Sekizuka T, Komase K, Kuroda M, Hasegawa H, Kawaoka Y, Tashiro M, Takeda M.
  • Organizer: The 13th Awaji International Forum on Infection and Immunity in Nara.
  • Place of Presentation: Nara, Japan
  • Year and Date: 2014-09-23 – 2014-09-26
• [Presentation] The host protease TMPRSS2 plays a major role for influenza virus replication in vivo. (2014)
  • Author(s): 90.Sakai K, Ami Y, Tahara M, Kubota T, Nakajima N, Kuroda M, Hasegawa H, Kawaoka Y, Tashiro M, Takeda M.
  • Organizer: 16th IUMS International Congress of Virology.
  • Place of Presentation: Montreal, Canada
  • Year and Date: 2014-07-27 – 2014-08-01
• [Remarks] ウイルス第三部
  • URL: http://www.nih.go.jp/niid/ja/from-vir3.html