在ANP32A中的物种差异是流感A病毒聚合酶宿主限制的基础
Jason S Long1, Efstathios S Giotis1, Olivier Moncorgé2
1Section of Virology, Department of Medicine, Imperial College London, St Mary's Campus, London W2 1PG, UK.
Nature
|January 8, 2016
概括
由于宿主蛋白ANP32A的差异,禽流感病毒聚合酶在人类细胞中发生斗争. 修改ANP32A允许禽流感病毒复制,使其成为潜在的抗病毒目标.
科学领域:
- 病毒学
- 分子生物学
- 免疫学
背景情况:
- 流感大流行源于适应人类传播的动物病毒.
- 宿主障碍,包括受体结合和聚合酶活性,限制了禽流感病毒在哺乳动物中的适应.
- 哺乳动物溢出过程中病毒聚合酶适应的作用尚不清楚.
研究的目的:
- 研究宿主因子在哺乳动物细胞中的禽流感病毒聚合酶功能中的作用.
- 确定限制人类禽流感病毒复制的特定宿主蛋白不相容性.
- 确定病毒聚合酶适应哺乳动物宿主的机制.
主要方法:
- 对鸟类和哺乳动物ANP32A蛋白结构和功能的比较分析.
- 对ANP32A的局部定向突变,以评估其对病毒聚合酶活性的影响.
- 在不同宿主细胞环境中测量病毒RNA-依赖RNA聚合酶活性.
- 在适应哺乳动物宿主过程中选择的病毒突变的分析.
主要成果:
- 在ANP32A中存在特定物种的差异,特别是鸟类特有的33-氨基酸插入,解释了哺乳动物细胞中鸟类聚合酶的低最佳活性.
- 鸟类ANP32A在哺乳动物细胞中挽救鸟类聚合酶功能,而插入的删除则取消了这种挽救.
- 将鸟类特异序列插入人类ANP32A或ANP32B支持鸟类聚合酶功能.
- 关键的病毒突变,如PB2 ((E627K),有助于适应较短的哺乳动物ANP32A.
结论:
- ANP32A 是一个关键的宿主因子,可使流感病毒复制.
- 种类之间的ANP32A结构变化是宿主范围的关键决定因素.
- 抗流感新型抗病毒策略的潜在宿主向目标是ANP32A.
- 了解ANP32A的功能对于预测和控制流感流行风险至关重要.
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