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

鉴定负责在人类中有效复制的流感病毒突变并分析突变对动物模型致病性的影响

• 批准号: 22790426
• 负责人: YAMADA Shinya
• 金额: $ 2.5万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2010
• 资助国家: 日本
• 起止时间: 2010 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22790426/
• 关键词: インフルエンザ; 伝播; 変異

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.

H5N1病毒在人类之间的有效传播从未发生过，这表明需要进一步适应人类。目前，对H5N1病毒在人类中有效传播的突变知之甚少。聚合酶亚基PB2蛋白中的两个氨基酸（位置627的赖氨酸或位置701的天冬酰胺）被认为对于禽流感A病毒适应哺乳动物至关重要。然而，最近出现的大流行性H1N1病毒缺乏这些氨基酸。在这里，我们报告PB 2第591位的碱性氨基酸可以弥补第627位赖氨酸的缺乏，并使哺乳动物中的大流行性H1N1病毒能够有效复制。此外，PB2的591位的碱性氨基酸显著增加了禽H5N1病毒在小鼠中的致死性，我们还报道了2004年从越南人分离的H5N1病毒通过获得几个突变，通过在正常人支气管上皮细胞（NHBE）中传代而变得更高。主要是血凝素（HA）基因的突变负责他们的高增长。然而，在雪貂模型中没有观察到突变病毒通过呼吸道飞沫传播。在本研究中，我们发现了一些新的分子标记，这些标记负责流感病毒在人类细胞中的有效复制。

项目成果

[Virological characteristics of pandemic (H1N1) 2009 influenza virus].

2009年甲型H1N1流感病毒的病毒学特征。

• DOI: 10.2222/jsv.60.3
• 发表时间: 2010
• 期刊: Uirusu
• 作者: T. Horimoto;Shinya Yamada;Y. Kawaoka
• 通讯作者: Y. Kawaoka

Transmissibility and pathogenicity of influenza viruses.

流感病毒的传播性和致病性。

• 发表时间: 2010
• 期刊: Nihon Rinsho
• 作者: Horimoto T;Yamada S;Kawaoka Y.
• 通讯作者: Kawaoka Y.

Influenza A (H5N1) viruses from pigs, Indonesia.

• DOI: 10.3201/eid1610.100508
• 发表时间: 2010-10
• 期刊: Emerging infectious diseases
• 影响因子: 11.8
• 作者: Nidom CA;Takano R;Yamada S;Sakai-Tagawa Y;Daulay S;Aswadi D;Suzuki T;Suzuki Y;Shinya K;Iwatsuki-Horimoto K;Muramoto Y;Kawaoka Y
• 通讯作者: Kawaoka Y

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

影响流感病毒致病性和传播性的因素

• 发表时间: 2011
• 作者: 山田晋弥;河岡義裕
• 通讯作者: 河岡義裕

-感染症の病因病態、遺伝子制御、シグナル伝達

- 传染病的发病机制、基因调控和信号转导

• 发表时间: 2010
• 作者: Yamada S;et al.;山田晋弥;山田晋弥;山田晋弥
• 通讯作者: 山田晋弥