Adaptive mutations in NEP compensate for defective H5N1 RNA replication in cultured human cells
Adaptive mutations in NEP compensate for defective H5N1 RNA replication in cultured human cells
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DOI：
10.1038/ncomms1804
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发表时间：
2012-05-01
影响因子：
16.6
通讯作者：
Schwemmle, Martin
中科院分区：
文献类型：
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作者：
Maenz, Benjamin;Brunotte, Linda;Schwemmle, Martin
禽流感病毒感染哺乳动物需要适应性突变，以实现在新宿主中的高水平复制。然而，这种适应过程的基本机制仍然是未知的。在这里，我们表明，禽聚合酶，缺乏人类的签名PB 2-E627 K，是无法产生可用的互补RNA模板在培养的人类细胞，因此需要适应。保留禽PB 2-E627的高致病性人H5 N1分离株A/Thailand/1（KAN-1）/2004的表征揭示RNA复制中的缺陷仅部分地由聚合酶中的突变补偿。相反，核输出蛋白的突变是有效的聚合酶活性所必需的。我们证明了几种人类分离物的核输出蛋白的适应性突变增强了人类培养细胞中禽类聚合酶的聚合酶活性。总之，当跨越物种屏障时，禽流感病毒在核输出蛋白中获得适应性突变，以逃避哺乳动物细胞中受限的病毒基因组复制。
Infection of mammals by avian influenza viruses requires adaptive mutations to achieve high-level replication in the new host. However, the basic mechanism underlying this adaptation process is still unknown. Here we show that avian polymerases, lacking the human signature PB2-E627K, are incapable of generating usable complementary RNA templates in cultured human cells and therefore require adaptation. Characterization of the highly pathogenic human H5N1 isolate A/Thailand/1(KAN-1)/2004 that retained the avian PB2-E627 reveals that the defect in RNA replication is only partially compensated by mutations in the polymerase. Instead, mutations in the nuclear export protein are required for efficient polymerase activity. We demonstrate that adaptive mutations in nuclear export proteins of several human isolates enhance the polymerase activity of avian polymerases in human cultured cells. In conclusion, when crossing the species barrier, avian influenza viruses acquire adaptive mutations in nuclear export protein to escape restricted viral genome replication in mammalian cells.