Instituto de Investigaciones Biotecnológicas, Universidad Nacional de San Martín, Buenos Aires, Argentina.
Institut Pasteur, Viruses and RNA Interference Unit, Centre National de la Recherche Scientifique UMR 3569, Paris, France.
PLoS Pathog. 2019 Apr 15;15(4):e1007706. doi: 10.1371/journal.ppat.1007706. eCollection 2019 Apr.
The potential of RNA viruses to adapt to new environments relies on their ability to introduce changes in their genomes, which has resulted in the recent expansion of re-emergent viruses. Chikungunya virus is an important human pathogen transmitted by mosquitoes that, after 60 years of exclusive circulation in Asia and Africa, has rapidly spread in Europe and the Americas. Here, we examined the evolution of CHIKV in different hosts and uncovered host-specific requirements of the CHIKV 3'UTR. Sequence repeats are conserved at the CHIKV 3'UTR but vary in copy number among viral lineages. We found that these blocks of repeated sequences favor RNA recombination processes through copy-choice mechanism that acts concertedly with viral selection, determining the emergence of new viral variants. Functional analyses using a panel of mutant viruses indicated that opposite selective pressures in mosquito and mammalian cells impose a fitness cost during transmission that is alleviated by recombination guided by sequence repeats. Indeed, drastic changes in the frequency of viral variants with different numbers of repeats were detected during host switch. We propose that RNA recombination accelerates CHIKV adaptability, allowing the virus to overcome genetic bottlenecks within the mosquito host. These studies highlight the role of 3'UTR plasticity on CHIKV evolution, providing a new paradigm to explain the significance of sequence repetitions.
RNA 病毒适应新环境的潜力依赖于它们在基因组中引入变化的能力,这导致了最近新兴病毒的扩张。基孔肯雅病毒是一种由蚊子传播的重要人类病原体,在亚洲和非洲 exclusive circulation 60 年后,它已迅速传播到欧洲和美洲。在这里,我们研究了 CHIKV 在不同宿主中的进化,并揭示了 CHIKV 3'UTR 的宿主特异性要求。CHIKV 3'UTR 上的序列重复是保守的,但在不同的病毒谱系中重复序列的拷贝数有所不同。我们发现,这些重复序列块通过复制选择机制促进 RNA 重组,该机制与病毒选择协同作用,决定了新病毒变体的出现。使用一组突变病毒的功能分析表明,蚊子和哺乳动物细胞中的相反选择压力在传播过程中施加了适应性成本,而由序列重复引导的重组减轻了这种成本。事实上,在宿主转换过程中,具有不同重复次数的病毒变体的频率发生了剧烈变化。我们提出,RNA 重组加速了 CHIKV 的适应性,使病毒能够克服蚊子宿主中的遗传瓶颈。这些研究强调了 3'UTR 可塑性在 CHIKV 进化中的作用,为解释序列重复的意义提供了一个新的范例。