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首页> 外文期刊>PLoS Genetics >CRISPR/Cas9 modified An. gambiae carrying kdr mutation L1014F functionally validate its contribution in insecticide resistance and combined effect with metabolic enzymes
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CRISPR/Cas9 modified An. gambiae carrying kdr mutation L1014F functionally validate its contribution in insecticide resistance and combined effect with metabolic enzymes

机译：CRISPR / CAS9修改了<斜体切换=“是”> 。 <斜体切换=“是”>冈比亚携带<斜体切换=“是”> KDR 突变L1014F在功能上验证其对杀虫剂抗性的贡献和与代谢酶的组合效应

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Insecticide resistance in Anopheles mosquitoes is a major obstacle in maintaining the momentum in reducing the malaria burden; mitigating strategies require improved understanding of the underlying mechanisms. Mutations in the target site of insecticides (the voltage gated sodium channel for the most widely used pyrethroid class) and over-expression of detoxification enzymes are commonly reported, but their relative contribution to phenotypic resistance remain poorly understood. Here we present a genome editing pipeline to introduce single nucleotide polymorphisms in An . gambiae which we have used to study the effect of the classical kdr mutation L1014F (L995F based on An . gambiae numbering), one of the most widely distributed resistance alleles. Introduction of 1014F in an otherwise fully susceptible genetic background increased levels of resistance to all tested pyrethroids and DDT ranging from 9.9-fold for permethrin to &24-fold for DDT. The introduction of the 1014F allele was sufficient to reduce mortality of mosquitoes after exposure to deltamethrin treated bednets, even as the only resistance mechanism present. When 1014F was combined with over-expression of glutathione transferase Gste2, resistance to permethrin increased further demonstrating the critical combined effect between target site resistance and detoxification enzymes in vivo . We also show that mosquitoes carrying the 1014F allele in homozygosity showed fitness disadvantages including increased mortality at the larval stage and a reduction in fecundity and adult longevity, which can have consequences for the strength of selection that will apply to this allele in the field. Author summary Escalation of pyrethroid resistance in Anopheles mosquitoes threatens to reduce the effectiveness of our most important tools in malaria control. Studying the mechanisms underlying insecticide resistance is critical to design mitigation strategies. Here, using genome modified mosquitoes, we functionally characterize the most prevalent mutation in resistant mosquitoes, showing that it confers substantial levels of resistance to all tested pyrethroids and undermines the performance of pyrethroid-treated nets. Furthermore, we show that combining this mutation with elevated levels of a detoxification enzyme further increases resistance. The pipeline we have developed provides a robust approach to quantifying the contribution of different combinations of resistance mechanisms to the overall phenotype, providing the missing link between resistance monitoring and predictions of resistance impact.
机译：蚊虫抗性蚊子是维持降低疟疾负担的势头的主要障碍;减轻策略需要改善对潜在机制的理解。通常报道杀虫剂靶部位（用于最广泛使用的拟除虫菊酯类的电压门控钠通道的突变，但它们对排毒酶的过表达，但它们对表型抗性的相对贡献仍然明显。在这里，我们提出了一种基因组编辑管线，以引入单一核苷酸多态性。冈比亚我们用于研究经典KDR突变L1014F（基于冈比亚编号的L995F）的效果，是最广泛分布的阻力等位基因之一。引入1014F在另一种完全敏感的遗传背景上增加了所有测试拟除虫菊酯和DDT的抗性水平，从9.9倍的渗透素到＆amp; 24倍用于DDT。在暴露于临氨甲菊处理的蚊帐后，1014F等位基因的引入足以减少蚊子的死亡率，即使作为存在的唯一电阻机制。当1014F与谷胱甘肽转移酶GSTE2的过表达相结合时，对渗透素的抗性进一步增加了体内靶部位抗性和排毒酶之间的临界综合效应。我们还表明，潜在蚊子在纯合子中携带1014F等位基因显示健身缺点，包括幼虫阶段的死亡率增加，繁殖力和成年寿命减少，这可能对该等位基因的选择强度产生后果。作者摘要促进灭蚊虫的丙酮抗性抵抗潜在蚊子威胁要降低疟疾控制中最重要的工具的有效性。研究杀虫剂抗性的潜在机制对于设计缓解策略至关重要。在这里，使用基因组改性蚊子，我们在功能上表征了抗性蚊子中最普遍的突变，表明它赋予所有测试的拟除虫菊酯的大量抗性水平，并破坏了拟除虫治疗网的性能。此外，我们表明，将这种突变与解毒酶的升高进行了进一步增加了抗性。我们开发的管道提供了一种稳健的方法来量化不同组合对整个表型的不同组合的贡献，提供阻力监测与阻力冲击预测之间的缺失联系。

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