Pattern of mutation in the genome of influenza A virus on adaptation to increased virulence in the mouse lung: Identification of functional themes
Pattern of mutation in the genome of influenza A virus on adaptation to increased virulence in the mouse lung: Identification of functional themes
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DOI：
10.1073/pnas.111165798
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发表时间：
2001-06-05
影响因子：
11.1
通讯作者：
Nesrallah, M
中科院分区：
文献类型：
--
作者：
Brown, EG;Liu, H;Nesrallah, M
流感病毒毒力的遗传基础在很大程度上是未知的。为了探索肺毒力增加的突变基础，研究了H3N2临床原型分离物A/HK/1/68。被老鼠适应了。据我们所知，基因组测序首次证明，一组11个突变可以将一种无毒病毒转化为一种可以在最小剂量下致死的毒性变异病毒。在克隆分离株中检测到的14个氨基酸替换中有13个（93%）可能有助于适应，因为它们的正选择、位于功能区域和/或独立发生在其他强毒流感病毒中。强毒变异体的突变反复涉及核定位信号和蛋白质和RNA相互作用的位点，表明它们是新的毒力调节剂。具有相同血凝素突变的小鼠适应变体具有不同的融合pH最佳值，表明血凝素的融合活性可以被其他病毒基因调节。实验适应导致选择了三种突变，这三种突变与强毒的人H5N1分离物A/HK/156/97相同，这可能有助于其产生极端毒力。通过序列传代分析病毒适应似乎提供了生物学相关突变的鉴定。
The genetic basis for virulence in influenza virus is largely unknown. To explore the mutational basis for increased virulence in the lung, the H3N2 prototype clinical isolate, A/HK/1/68. was adapted to the mouse. Genomic sequencing provided the first demonstration, to our knowledge, that a group of 11 mutations can convert an avirulent virus to a virulent variant that can kill at a minimal dose. Thirteen of the 14 amino acid substitutions (93%) detected among clonal isolates were likely instrumental in adaptation because of their positive selection, location in functional regions, and/or independent occurrence in other virulent influenza viruses, Mutations in virulent variants repeatedly involved nuclear localization signals and sites of protein and RNA interaction, implicating them as novel modulators of virulence. Mouse-adapted variants with the same hemagglutinin mutations possessed different pH optima of fusion, indicating that fusion activity of hemagglutinin can be modulated by other viral genes. Experimental adaptation resulted in the selection of three mutations that were in common with the virulent human H5N1 isolate A/HK/156/97 and that may be instrumental in its extreme virulence. Analysis of viral adaptation by serial passage appears to provide the identification of biologically relevant mutations.