RNAi targeting of West Nile virus in mosquito midguts promotes virus diversification.
RNAi targeting of West Nile virus in mosquito midguts promotes virus diversification.
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DOI：
10.1371/journal.ppat.1000502
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发表时间：
2009-07
期刊：
影响因子：
6.7
通讯作者：
Ebel GD
中科院分区：
文献类型：
--
作者：
Brackney DE;Beane JE;Ebel GD
西尼罗河病毒（WNV）在自然界中作为一个遗传多样性的竞争基因组群体存在。这种高度的遗传多样性和随之而来的适应性可塑性促进了西尼罗河病毒对北美传播周期的快速适应，并促成了它在整个新世界的爆炸性传播。西尼罗河病毒在自然界中维持在蚊子和鸟类之间的传播周期中，蚊子的宿主内遗传多样性最高。蚊子遗传多样性增加的机制基础知之甚少。为了确定蚊子中WNV的高突变多样性是否由RNA干扰（RNAi）驱动，我们使用高通量，大规模平行测序和估计的病毒遗传多样性来表征经口暴露的致倦库蚊中肠中对WNV的RNAi反应。我们的数据表明，在经口暴露的载体蚊子中的WNV感染诱导RNAi途径，并且与弱靶向区域相比，更强烈地被RNAi靶向的WNV基因组区域更可能含有点突变。这些结果表明，在自然条件下，蚊子内的WNV的正选择在宿主RNAi反应高度靶向的区域中更强。此外，它们为蚊子在推动西尼罗河病毒多样化方面的相对重要性提供了机制基础。西尼罗河病毒（WNV）于1999年传入纽约州，此后传遍美洲。它在自然界中在成年雌性蚊子和鸟类之间传播，偶尔感染人类和马。在宿主体内，西尼罗河病毒以各种各样的密切相关的突变体存在。蚊子体内的西尼罗河病毒种群在遗传上比鸟类更为复杂。这种差异的原因尚不清楚，但可能与宿主的先天抗病毒反应有关。我们证明，西尼罗河病毒是有针对性的RNA干扰，在蚊子的高度序列特异性途径。此外，我们提供了在自然条件下这种靶向强度与病毒突变相关的数据。这些结果为蚊子中WNV种群的复杂性增加提供了一个机制解释：RNAi反应创造了一个有利于稀有基因型的细胞内环境。此外，我们的研究结果表明，遗传多样性的西尼罗河病毒种群可能比多样性较低的种群具有优势，因为它们为RNAi反应提供了更复杂的靶标。最后，这些数据表明，西尼罗河病毒，可能还有其他具有高突变率的病毒，可能会逃脱高度序列特异性的工程抗病毒干预。
West Nile virus (WNV) exists in nature as a genetically diverse population of competing genomes. This high genetic diversity and concomitant adaptive plasticity has facilitated the rapid adaptation of WNV to North American transmission cycles and contributed to its explosive spread throughout the New World. WNV is maintained in nature in a transmission cycle between mosquitoes and birds, with intrahost genetic diversity highest in mosquitoes. The mechanistic basis for this increase in genetic diversity in mosquitoes is poorly understood. To determine whether the high mutational diversity of WNV in mosquitoes is driven by RNA interference (RNAi), we characterized the RNAi response to WNV in the midguts of orally exposed Culex pipiens quinquefasciatus using high-throughput, massively parallel sequencing and estimated viral genetic diversity. Our data demonstrate that WNV infection in orally exposed vector mosquitoes induces the RNAi pathway and that regions of the WNV genome that are more intensely targeted by RNAi are more likely to contain point mutations compared to weakly targeted regions. These results suggest that, under natural conditions, positive selection of WNV within mosquitoes is stronger in regions highly targeted by the host RNAi response. Further, they provide a mechanistic basis for the relative importance of mosquitoes in driving WNV diversification. West Nile virus (WNV) was introduced into New York state in 1999 and has since spread across the Americas. It is transmitted in nature between adult female mosquitoes and birds and occasionally infects humans and horses. Within the host, WNV exists as a diverse assortment of closely related mutants. WNV populations within mosquitoes are more complex genetically than are those within birds. The reasons for this discrepancy are unknown, but may be related to the host's innate antivirus response. We demonstrate that WNV is targeted by RNA interference, a highly sequence-specific pathway in the mosquito. Further, we present data that correlates the intensity of this targeting with virus mutation under natural conditions. These results provide a mechanistic explanation for the increasead complexity of WNV populations in mosquitoes: the RNAi response creates an intracellular environment where rare genotypes are favored. In addition, our results suggest that genetically diverse WNV populations may have an advantage over less diverse populations because they present a more complex target for the RNAi response. Finally, these data suggest that WNV, and possibly other viruses with high mutation rates, may escape an engineered antivirus intervention that is highly sequence-specific.
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影响因子：
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作者：
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DOI：
10.4269/ajtmh.2009.80.85
发表时间：
2009-01-01
影响因子：
3.3
作者：
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通讯作者：
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影响因子：
3.8
作者：
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通讯作者：
Ebel, GD