Identification of influenza virus mutations responsible for the efficient replication in humans and analysis of the effect of the mutations on pathogenicity in animal models

2011 Fiscal Year Final Research Report

• Project/Area Number: 22790426
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Virology
• Research Institution: The University of Tokyo
• Principal Investigator: YAMADA Shinya 東京大学, 医科学研究所, 特任助教 (90466839)
• Project Period (FY): 2010 – 2011
• Keywords: インフルエンザ / 伝播 / 変異

Research Abstract

The efficient transmission of H5N1 viruses among humans has never occurred, suggesting that the further adaptation to humans is required. At the moment, little is known about mutations responsible for the efficient transmission of H5N1 viruses in humans. Two amino acids(lysine at position 627 or asparagine at position 701) in the polymerase subunit PB2 protein are considered critical for the adaptation of avian influenza A viruses to mammals. However, the recently emerged pandemic H1N1 viruses lack these amino acids. Here, we report that a basic amino acid at position 591 of PB2 can compensate for the lack of lysine at position 627 and confers efficient viral replication to pandemic H1N1 viruses in mammals. Moreover, a basic amino acid at position 591 of PB2 substantially increased the lethality of an avian H5N1 virus in mice.
We also report that H5N1viruses isolated from human in Vietnam in 2004 became to grow higher through the passages in normal human bronchus epithelial(NHBE) cells by acquiring several mutations. Mainly mutations in hemagglutinin(HA) genes were responsible for their high growth. However, no transmission of the mutant viruses via respiratory droplets in ferret model was observed.
In this study, we identified some new molecular markers responsible for the efficient replication of influenza viruses in human cells.

Research Products

• [Journal Article] Adaptation of a duck influenza A virus in quail. (2012)
  • Author(s): Yamada S, Shinya K, Takada A, Ito T, Suzuki T, Suzuki Y, Le QM, Ebina M, Kasai N, Kida H, Horimoto T, Rivailler P, Chen LM, Donis RO, Kawaoka Y.
  • Journal Title: J Virol Volume: 86(3) Pages: 1411-20
  • URL: http://jvi.asm.org/content/86/3/1411.long
  • Peer Reviewed
• [Journal Article] Avian-type receptor-binding ability can increase influenza virus pathogenicity in macaques (2011)
  • Author(s): Watanabe T, Shinya K, Watanabe S, Imai M, Hatta M, Li C, Wolter BF, Neumann G, Hanson A, Ozawa M, Yamada S, Imai H, et al
  • Journal Title: J Virol
  • URL: http://jvi.asm.org/content/85/24/13195.long
  • Peer Reviewed
• [Journal Article] Replication-incompetent influenza A viruses that stably express a foreign gene. (2011)
  • Author(s): Ozawa M, Victor ST, Taft AS, Yamada S, Li C, Hatta M, Das SC, Takashita E, Kakugawa S, Maher EA, Neumann G, Kawaoka Y.
  • Journal Title: J Gen Virol
  • URL: http://vir.sgmjournals.org/content/92/12/2879.long
  • Peer Reviewed
• [Journal Article] The nucleoprotein and matrix protein segments of H5N1 influenza viruses are responsible for dominance in embryonated eggs (2011)
  • Author(s): Shimizu K, Li C, Muramoto Y, Yamada S, Arikawa J, Chen H, Kawaoka Y.
  • Journal Title: J Gen Virol Volume: 92 Pages: 1645-9
  • URL: http://vir.sgmjournals.org/content/92/7/1645.long
  • Peer Reviewed
• [Journal Article] Bological and structural characterization of a host-adapting amino acid in influenza virus (2010)
  • Author(s): Yamada S, Hatta M, Staker BL, et al.
  • Journal Title: PLoS Pathog Volume: 6(8) Pages: e1001034
  • URL: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2916879/?tool=pubmed
  • Peer Reviewed
• [Journal Article] Influenza A(H5N1) viruses from pigs, Indonesia (2010)
  • Author(s): Nidom CA, Takano R, Yamada S, et al.
  • Journal Title: Emerg Infect Dis Volume: 16(10) Pages: 1515-23
  • URL: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3294999/?tool=pubmed
  • Peer Reviewed
• [Journal Article] High level of genetic compatibility between swine-origin H1N1 and highly pathogenic avian H5N1 influenza viruses (2010)
  • Author(s): Octaviani CP, Ozawa M, Yamada S, Goto H, Kawaoka Y.
  • Journal Title: J Virol Volume: 84(20) Pages: 10918-22
  • URL: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2950597/?tool=pubmed
  • Peer Reviewed
• [Journal Article] The HA and NS genes of human H5N1 influenza A virus contribute to high virulence in ferrets (2010)
  • Author(s): Imai H, Shinya K, Takano R, Kiso M, Muramoto Y, Sakabe S, Murakami S, Ito M, Yamada S, Le MT, Nidom CA, et al.
  • Journal Title: PLoS Pathog Volume: 6(9) Pages: e1001106
  • URL: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940759/?tool=pubmed
  • Peer Reviewed
• [Journal Article] Virological characteristics of pandemic(H1N1) 2009 influenza virus (2010)
  • Author(s): Horimoto T, Yamada S, Kawaoka Y.
  • Journal Title: Uirusu Volume: 60(1) Pages: 3-8
  • URL: https://www.jstage.jst.go.jp/article/jsv/60/1/60_1_3/_article
• [Journal Article] Transmissibility and pathogenicity of influenza viruses. (2010)
  • Author(s): Horimoto T, Yamada S, Kawaoka Y.
  • Journal Title: Nihon Rinsho Volume: 68(9) Pages: 1616-23
  • URL: http://www.ncbi.nlm.nih.gov/pubmed/20845737
• [Presentation] 新興・再興感染症研究拠点形成プログラム (2012)
  • Author(s): 山田晋弥
  • Organizer: 新興・再興感染症に関するアジアリサーチフォーラム-2012
  • Place of Presentation: 神戸(兵庫)
  • Year and Date: 20120110-12
• [Presentation] (2011)
  • Author(s): 山田晋弥
  • Organizer: 第8回日中連携研究室ワークショップ
  • Place of Presentation: 北京(中華人民共和国)
  • Year and Date: 20111120-22
• [Presentation] 新興・再興感染症研究拠点形成プログラム (2010)
  • Author(s): 山田晋弥
  • Organizer: 新興・再興感染症に関するアジアリサーチフォーラム-2011
  • Place of Presentation: ハノイ(ベトナム)
  • Year and Date: 20101111-13
• [Presentation] -感染症の病因病態、遺伝子制御、シグナル伝達 (2010)
  • Author(s): 山田晋弥
  • Organizer: 第7回日中連携研究室ワークショップ
  • Place of Presentation: 北京(中華人民共和国)
  • Year and Date: 20101024-26
• [Book] インフルエンザウイルスの病原性と伝播性に関与する因子 (2011)
  • Author(s): 山田晋弥、河岡義裕
  • Total Pages: 6
  • Publisher: 薬局(南山堂)
• [Book] レスピレーションリサーチファンデーション (2010)
  • Author(s): 山田晋弥、河岡義裕
  • Total Pages: 7