Analysis of replication mechanisms of acute respiratory viruses in epithelia

• Project/Area Number: 23390114
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• 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): 關 文緒 ; 酒井 宏治 ; 田原 舞乃 ; 中津 祐一郎 ; 大槻 紀之
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥19,370,000 (Direct Cost: ¥14,900,000、Indirect Cost: ¥4,470,000); Fiscal Year 2013: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2012: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000); Fiscal Year 2011: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• Keywords: 病原性 / 感染症 / ウイルス / 微生物 / プロテアーゼ / 開裂 / 膜融合

Research Abstract

Our studies revealed that canine distemper virus (CDV) use nectin-4 to enter epithelial and neural cells. Recently CDV has caused lethal outbreaks in monkeys. Our studies revealed that CDV has the ability to use monkey receptors as well as dog receptors. In addition, it became able to use human receptors, when it acquired a single amino acid substitution in the H protein. Also our studies showed that CDV intrinsically has the ability to counteract the human innate immune system.
We have generated TMPRSS2 kockout mice. In the mice, cleavage of influenza virus HA protein was severely restricted. These data show that TMPRSS2 is the essential protease that activates influenza virus in vivo.

Research Products

• [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, Kawaoka Y, Tashiro M, Takeda M
  • Journal Title: J Virol Volume: 88 Pages: 5608-16
• [Journal Article] Lethal canine distemper virus outbreak in cynomolgus monkeys in Japan in 2008 (2013)
  • Author(s): Sakai K, Nagata N, Ami Y, Seki F, Suzaki Y, Iwata-Yoshikawa N, Suzuki T, Fukushi S, Mizutani T, Yoshikawa T, Otsuki N, Kurane I, Komase K, Yamaguchi R, Hasegawa H, Saijo M, Takeda M, Morikawa S
  • Journal Title: J. Virol Volume: 87 Pages: 1105-14
• [Journal Article] Canine distemper virus with the intact C protein has the potential to replicate in human epithelial cells by using human nectin4 as a receptor (2013)
  • Author(s): Otsuki N, Sekizuka T, Seki F, Sakai K, Kubota T, Nakatsu Y, Chen S, Fukuhara H, Maenaka K, Yamaguchi R, Kuroda M, Takeda M
  • Journal Title: Virology Volume: 435 Pages: 485-92
• [Journal Article] Functional and structural characterization of neutralizing epitopes of measles virus hemagglutinin protein (2013)
  • Author(s): Tahara M, Ito Y, Brindley M, Ma X, He J, Xu S, Fukuhara H, Sakai K, Komase K, Rota P, Plemper R, Maenaka K, Takeda M
  • Journal Title: J. Virol Volume: 87 Pages: 666-75
• [Journal Article] The receptor-binding site of the measles virus hemagglutinin protein itself constitutes a conserved neutralizing epitope (2013)
  • Author(s): Tahara M, Ohno S, Sakai K, Ito Y, Fukuhara H, Komase K, Brindley MA, Rota PA, Plemper RK, Maenaka K, Takeda M
  • Journal Title: J Virol Volume: 87 Pages: 3583-6
• [Journal Article] Intracellular transport of the measles virus RNP complex is mediated by Rab11A-positive recycling endosomes and drives virus release from the apical membrane of polarized epithelial cells (2013)
  • Author(s): Nakatsu Y, Ma X, Seki F, Suzuki T, Iwasaki M, Yanagi Y, Komase K, Takeda M
  • Journal Title: J Virol Volume: 87 Pages: 4683-93
• [Journal Article] Canine distemper virus associated with a lethal outbreak in monkeys can readily adapt to use human receptors (2013)
  • Author(s): Sakai K, Yoshikawa T, Seki F, Fukushi S, Tahara M, Nagata N, Ami Y, Mizutani T, Kurane I, Yamaguchi R, Hasegawa H, Saijo M, Komase K, Morikawa S, Takeda M
  • Journal Title: J Virol Volume: 87 Pages: 7170-5
• [Journal Article] TMPRSS2 is an activating protease for respiratory parainfluenza viruses (2013)
  • Author(s): Abe M, Tahara, Sakai K, Yamaguchi H, Kanou K, Shirato K, Kawase M, Noda M, Kimura H, Matsuyama S, Fukuhara H, Mizita K, Maenaka K, Ami Y, Esumi M, Kato A, Takeda M
  • Journal Title: J Virol Volume: 87 Pages: 11930-5
• [Journal Article] The V protein of canine distemper virus is required for virus replication in human epithelial cells (2013)
  • Author(s): Otsuki N, Nakatsu Y, Kubota T, Sekizuka T, Seki F, Sakai K, Kuroda M, Yamaguchi R, Takeda M
  • Journal Title: PLoS One Volume: 8
• [Journal Article] TMPRSS2 is an activating protease for respiratory parainfluenza viruses. (2013)
  • Author(s): Abe M, Tahara M, Sakai K, Yamaguchi H, Kanou K, Shirato K, Kawase M, Noda M, Kimura H, Matsuyama S, Fukuhara H, Mizuta K, Maenaka K, Ami Y, Esumi M, Kato A, Takeda M.
  • Journal Title: J Virol Volume: 87 Issue: 21 Pages: 11930-11935
  • DOI: 10.1128/jvi.01490-13
  • Peer Reviewed
• [Journal Article] Nectin4 is an epithelial cell receptor for canine distemper virus and involved in the neurovirulence (2012)
  • Author(s): Pratakpiriya W, Seki F, Otsuki N, Sakai K, Fukuhara H, Katamoto H, Hirai T, Maenaka K, Techangamsuwan S, Lan NT, Takeda M, Yamaguchi R
  • Journal Title: J Virol Volume: 86 Pages: 10207-10
• [Presentation] Canine distemper virus intrinsically uses monkey receptors and readily adapts to use human receptors as well (2013)
  • Author(s): Sakai K, Seki F, Tahara M, Otsuki N, Ami Y, Saijo M, Yamaguchi R, Komase K, Takeda M, Morikawa S
  • Organizer: 15th International Conference on Emerging Infectious Diseases (EID) in the Pacific Rim
  • Place of Presentation: Singapore
• [Presentation] Importance of the P2 and P3 residues of fusion proteins of respiratory viruses for their proteolytic activation by TMPRSS2 (2013)
  • Author(s): Tahara M, Abe M, Sakai K, Shirato K, Kanou K, Matsuyama S, Fukuhara H, Maenaka K, Ami Y, Esumi M, Kato A, Takeda M
  • Organizer: Negative Strand Virus Meeting 2013
  • Place of Presentation: Granada, Spain
• [Presentation] Both the C and V proteins of canine distemper virus play essential roles for the virus replication in human epithelial cells (2013)
  • Author(s): Otsuki N, Sekizuka T, Kubota T, Nakatsu Y, Seki F, Sakai K, Yamaguchi R, Fukuhara H, Maenaka K, Kuroda M, Takeda M
  • Organizer: Negative Strand Virus Meeting 2013
  • Place of Presentation: Granada, Spain
• [Presentation] High potential of canine distemper virus in the ability to use macaca and human receptors (2013)
  • Author(s): Sakai K, Seki F, Tahara M, Otsuki N, Ami Y, Yamaguchi R, Saijo M, Komase K, Morikawa S, Takeda M
  • Organizer: Negative Strand Virus Meeting 2013
  • Place of Presentation: Granada, Spain
• [Presentation] 呼吸器感染症ウイルスの病原性発現理解が拓くワクチン開発と創薬への道 (2013)
  • Author(s): 竹田誠
  • Organizer: 北海道大学創薬ネットワークセミナー
  • Place of Presentation: 札幌
• [Presentation] 130. 呼吸器感染症ウイルス増殖におけるTMPRSS2の役割ならびに膜融合タンパクP3位保存グルタミンの重要性について (2013)
  • Author(s): 竹田誠
  • Organizer: 2nd Negative Strand Virus-Japan Symposium
  • Place of Presentation: 沖縄、宜野湾市
• [Presentation] パラインフルエンザウイルス及びインフルエンザウイルス感染における膜貫通型セリンプロテアーゼTMPESS2の生体内での役割解明 (2012)
  • Author(s): 安部昌子, ら
  • Organizer: First Negative Strand Virus-Japan Symposium
  • Place of Presentation: 長崎
  • Year and Date: 2012-01-22
• [Presentation] Proteolytic activation of the fusion protein of human and murine parainfluenza viruses by the type II transmembrane serine protease TMPRSS2 (2012)
  • Author(s): Abe M, Kato A, Sakai K, Kanou K, Mizuta K, Shirato K, Matsuyama S, Takeda M
  • Organizer: 31st Annual Meeting for American Society for Virology
  • Place of Presentation: Madison, WI, USA
• [Presentation] Measles virus utilizes the cellular microtubule network and specific endosomes for transport of the RNP complex, matrix protein and H glycoprotein (2012)
  • Author(s): Nakatsu Y, Ma X, Seki F, Suzuki T, Iwasaki M, Yanagi Y, Komase K, Takeda M
  • Organizer: 31st Annual Meeting for American Society for Virology
  • Place of Presentation: Madison, WI, USA
• [Presentation] A structural and biochemical basis for the single serotype nature of measles virus (2012)
  • Author(s): Tahara M, Ito Y, Brindley MA, Ma XM, He JL, Xu ST, Fukuhara H, Sakai K, Ohno S, Komase K, Rota PA, Plemper RK, Maenaka K, Takeda M
  • Organizer: The 11th Awaji International Forum on Infection and Immunity
  • Place of Presentation: Awaji Island, Hyogo, Japan
• [Presentation] Importance of the P3 glutamine residue for proteolytic activation of the fusion protein of parainfluenza viruses by TMPRSS2 (2012)
  • Author(s): Abe M, Kato A, Tahara M, Sakai K, Kanou K, Shirato K, Noda M, Kimura H, Ami Y, Matsuyama S, Mizuta K, Takeda M
  • Organizer: The 11th Awaji International Forum on Infection and Immunity
  • Place of Presentation: Awaji Island, Hyogo, Japan
• [Presentation] Canine distemper virus possesses an ability to use human nectin4 as a receptor (2012)
  • Author(s): Otsuki N, Sekizuka T, Seki F, Sakai K, Kubota T, Nakatsu N, Chen S, Fukuhara H, Maenaka K, Yamaguchi R, Kuroda M, Takeda M
  • Organizer: The 11th Awaji International Forum on Infection and Immunity
  • Place of Presentation: Awaji Island, Hyogo, Japan
• [Presentation] Structural and Functional Constraints on the Measles Virus Hemagglutinin Protein Prevent Escape from Neutralization (2012)
  • Author(s): Takeda M, Tahara M, Ito Y, Brindley MA, Fukuhara H, Komase K, Yanagi Y, Rota PA, Plemper RK, Maenaka K
  • Organizer: The 34th Naito Conference : Infection, Immunity and their Control for Health: Mucosal Barrier, Pathogen and Vaccine
  • Place of Presentation: Sapporo, Hokkaido
• [Presentation] Importance of the P3 glutamine residue for proteolytic activation of the fusion protein of parainfluenza viruses by TMPRSS2. (2012)
  • Author(s): Makoto Takeda
  • Organizer: The 11th Awaji International Forum on Infection and Immunity.
  • Place of Presentation: Awaji Island, Hyogo, Japan
• [Presentation] Proteolytic activation of the fusion protein of human and murine parainfluenza viruses by the type II transmembrane serine protease TMPRSS2. (2012)
  • Author(s): Makoto Takeda
  • Organizer: 31st Annual Meeting for American Society for Virology
  • Place of Presentation: Madison, WI, USA
• [Presentation] 膜貫通型セリンプロテアーゼTMPRSS2はパラインフルエンザウイルスF蛋白を活性化し増殖を促進する (2012)
  • Author(s): 竹田誠
  • Organizer: 第60回日本ウイルス学会
  • Place of Presentation: 大阪、大阪市
• [Presentation] The ribonucleoprotein complex of measles virus is transported via microtubule network and recycling endosome system without the support of the matrix protein (2011)
  • Author(s): Nakatsu Y, Ma X, Seki F, Suzuki T, Komase K, Takeda M
  • Organizer: Atlanta Area 5th Paramyxer
  • Place of Presentation: University of Georgia, Atlanta, GA, USA
  • Year and Date: 2011-12-02
• [Presentation] Measles virus escapes from neutralization at the cost of SLAM-binding activity (2011)
  • Author(s): Tahara M, Ma XM, He JL, Ito Y, Fukuhara H, Brindley MA, Sakai K, Yanagi Y, Komase K, Plemper RK, Rota PA, Maenaka K, Takeda M
  • Organizer: Atlanta Area 5th Paramyxer
  • Place of Presentation: University of Georgia, Atlanta, GA, USA
  • Year and Date: 2011-12-02
• [Presentation] Virulence of canine distemper virus isolated from cynomolgus monkeys during 2008 epizootic in Japan (2011)
  • Author(s): Sakai K, Nagata N, Ami Y, Komase K, Takeda M, Saijo M, Morikawa S
  • Organizer: 2011 Measles Virus Mini-Symposium
  • Place of Presentation: Mayo Clinic, Rochester, MN
  • Year and Date: 2011-07-15
• [Presentation] Antigenic determinants of Measles Virus Hemagglutinin associated with single serotype (2011)
  • Author(s): Tahara M, Komase K, Ma XM, He JL, Yanagi Y, Maenaka K, Rota PA, and Takeda M
  • Organizer: 2011 Measles Virus Mini-Symposium
  • Place of Presentation: ayo Clinic, Rochester, MN
  • Year and Date: 2011-07-15
• [Presentation] Virological and pathological analyses of canine distemper virus isolated from cynomolgus monkeys during 2008 epizootic in Japan (2011)
  • Author(s): Sakai K, Nagata N, Ami Y, Komase K, Takeda M, Saijyo M, Morikawa S
  • Organizer: 30th Annual Meeting of American Scociety for Virology
  • Place of Presentation: Minneapolis, Minnesota
• [Presentation] Conserved and variable antigenic sites on the mealses virus hemagglutinin protein (2011)
  • Author(s): Tahara M, Komase K, Yanagi Y, Maenaka K, Rota PA, Takeda M
  • Organizer: 30th Annual Meeting of American Scociety for Virology
  • Place of Presentation: Minneapolis, Minnesota
• [Presentation] Characterization of canine distemper virus isolated from cynomolgus monkeys during 2008 epizootic in Japan (2011)
  • Author(s): Sakai K, Nishio Y, Nagata N, Ami Y, Komae K, Shimojima M, Maeda K, Takeda M, Saijo M, Morikawa S
  • Organizer: International Union of Microbiological Societies 2011 Congress
  • Place of Presentation: Sapporo, Japan
• [Presentation] Identification of conserved neutralizing epitopes of the measles virus hemagglutinin protein located in proximity and distal to the receptor-binding site (2011)
  • Author(s): Tahara M, Komase K, Ma XM, He JL, Yanagi Y, Maenaka K, Rota PA, Takeda M
  • Organizer: International Union of Microbiological Societies 2011 Congress
  • Place of Presentation: Sapporo, Japan
• [Presentation] Intracellular Trafficking of the measles virus L protein occurs independently of the viral M protein and is related to microtubule network and recycling endosome (2011)
  • Author(s): Nakatsu Y, Ma XM, Seki F, Suzuki T, Komase K, Takeda M
  • Organizer: International Union of Microbiological Societies 2011 Congress
  • Place of Presentation: Sapporo, Japan
• [Presentation] Protein preparation and preliminary X-ray crystallographic study of hemagglutinin from canine distemper virus (2011)
  • Author(s): Ose T, Sako M, Kajikawa M, Hashiguchi T, Ito Y, Fukuhara H, Takeda M, Yanagi Y, Maenaka K
  • Organizer: International Union of Microbiological Societies 2011 Congress
  • Place of Presentation: Sapporo, Japan
• [Remarks]
  • URL: http://www.nih.go.jp/niid/ja/from-vir3.html
• [Remarks] 国立感染症研究所ウイルス第三部
  • URL: http://www.nih.go.jp/niid/ja/from-vir3.html
• [Remarks]
  • URL: http://www.nih.go.jp/niid/ja/