Selection upon Wolbachia-mediated dengue virus blocking in Aedes aegypti

The viruses that cause dengue fever, Zika and chikungunya are transmitted by the mosquito, Aedes aegypti and pose great threats to global public health. Current vaccines and treatments against these viruses as well as methods of mosquito control are limited in their efficacy and so novel interventions are needed to reduce disease transmission. Wolbachia are intracellular bacteria that are adapted to spread through insect populations and have been found to reduce viral replication in insects, a phenotype that is referred to as viral 'blocking'. Although not naturally found in A. aegypti, Wolbachia have been stably introduced into this mosquito via trans-infection over a decade ago and has since been shown to reduce the transmission potential of dengue, Zika and chikungunya. More recently, field trials in the tropics show that Wolbachia can spread through A. aegypti populations and reduce the local incidence of dengue fever. However, it remains unknown how stable this viral blocking phenotype will be in A. aegypti over time. We selected for low and high Wolbachia-mediated dengue blocking alongside a control treatment where mosquitoes were selected at random. Each treatment included 3 independent populations generated randomly from the same ancestral population of mosquitoes using a random number generator. Selection was performed for 4 generations.We reveal significant genetic variation in the A. aegypti genome that is associated with Wolbachia-mediated dengue blocking and responds rapidly to selection. In addition, we find that mosquitoes with weaker Wolbachia-mediated dengue blocking tend to have reduced fitness and appear to be selected against. Together, our data identify candidate genes that can shape Wolbachia-mediated viral blocking and suggest that there is potential for blocking to be maintained by selection. These results will both direct further research into and inform the use of Wolbachia as biocontrol agents against mosquito-borne viruses, including how to measure and improve their efficacy.

登革热、寨卡病毒与基孔肯雅热的病原体均由埃及伊蚊（Aedes aegypti）传播，对全球公共卫生构成严重威胁。当前针对这类病毒的疫苗、治疗方案以及蚊虫防控手段的防控效果均存在局限，因此亟需开发新型干预策略以降低疾病传播风险。
沃尔巴克氏体（Wolbachia）是一类可在昆虫种群中扩散的胞内细菌，研究发现其能够抑制昆虫体内的病毒复制，这一表型被称为病毒“阻断效应”。尽管埃及伊蚊天然不携带沃尔巴克氏体，但十余年前科研人员已通过转感染技术将其稳定导入该蚊虫体内，后续研究证实此举可降低登革热、寨卡病毒及基孔肯雅热的传播潜力。
近年来，热带地区的田间试验表明，沃尔巴克氏体可在埃及伊蚊种群中扩散，并降低当地登革热的发病率。但目前仍不清楚，随着时间推移，沃尔巴克氏体介导的病毒阻断效应在埃及伊蚊体内能否保持稳定。
本研究以随机选择蚊虫种群的处理作为对照，同时筛选出沃尔巴克氏体介导登革热阻断效应强弱各异的两组种群。每个处理组均设置3个独立种群，这些种群均由同一祖先蚊虫种群通过随机数生成器随机构建得到，筛选过程共开展4代。
研究发现，埃及伊蚊基因组中存在与沃尔巴克氏体介导的登革热阻断效应显著相关的遗传变异，且此类变异可对筛选过程做出快速响应。此外，本研究观察到，沃尔巴克氏体介导的登革热阻断效应较弱的蚊虫，其适合度往往更低，且易被自然选择淘汰。
综上，本研究通过实验数据鉴定出可调控沃尔巴克氏体介导的病毒阻断效应的候选基因，并提示可通过选择维持该阻断效应的稳定性。上述研究结果既可指导后续相关研究，也可为沃尔巴克氏体作为防控蚊媒病毒的生物防治剂的应用提供参考，包括如何评估并提升其防控效果。