Ecology and genetics of insecticide resistance in African malaria vectors

项目总结 标题：非洲疟疾病媒抗药性的生态学和遗传学 目前的一线媒介控制方法依赖于以拟除虫菊酯为基础的长效杀虫网(LLIN)和 室内滞留喷洒(IRS)。选择了抗药性载体的基因型，导致了广泛的 撒哈拉以南非洲地区的杀虫剂抗药性。杀虫剂抗药性的演变正在威胁着扭转 全球在控制疟疾方面取得的进展1.由于撒哈拉以南非洲地区对杀虫剂的抗药性日益增强，拟除虫菊酯-- 许多非洲国家最近推出了基于协同作用的下一代蚊帐，以克服 抗药性的挑战。这些蚊帐含有增效剂胡椒基丁醚(PBO)，它可以抑制 拟除虫菊酯解毒细胞色素P450酶与拟除虫菊酯代谢产物抑制络合物的活性 酵素。然而，关于非洲疟疾媒介如何应对该基因上的PBO暴露，人们知之甚少。 转录、生化和生物体水平。研究表明，在对杀虫剂敏感的果蝇中， PBO能够诱导P450和GST解毒基因家族的表达。增加的 通过PBO暴露产生P450和GST酶有可能增加对杀虫剂的耐受性。如果 疟疾病媒也是如此，PBO对减轻杀虫剂耐药性的影响是有限的。中环 继续使用杀虫剂的目的是为了更好地了解杀虫剂的生态学和遗传学 年在非洲主要疟疾媒介中面对拟除虫菊酯增效蚊帐引入的耐药性 我们在肯尼亚西部保留了精选的拟除虫菊酯抗性品系和PBO蚊帐，并在那里广泛使用 分布在一些县。为了实现这一目标，制定了三个目标。在目标1中，我们将研究 下一代PBO蚊帐对媒介生物学和减少传播的影响。来自此的数据将 告知PBO蚊帐在预先存在高拟除虫菊酯的地区减少传播的有效性 抵抗。在目标2中，我们将确定由于PBO蚊帐而导致蚊子表型变异的遗传基础。 这一目标将提供有关存在的不同抗药性机制的重要性的信息。 在肯尼亚西部，这对制定PBO净部署战略至关重要。在目标3中，我们将确定 拟除虫菊酯抗性疟疾对PBO暴露在基因转录和生化水平上的反应 向量。来自这一目标的数据可以提供关于PBO增效剂的遗传机制和风险的关键信息 在具有高耐药性的现场疟疾媒介种群中减少耐药性。总体而言，这三个目标将提供信息 PBO净部署战略、对减少输电的影响及其无法缓解的潜在风险 抵抗。

Project summary Title: Ecology and genetics of insecticide resistance in African malaria vectors The current first-line vector control methods rely on pyrethroid-based long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS). Insecticide-resistant vector genotypes are selected, leading to widespread of insecticide resistance in sub-Saharan Africa. The evolution of insecticide resistance is threatening to reverse the global gains in malaria control1,2. Due to the increasing insecticide resistance in sub-Saharan Africa, pyrethroid- based synergized next generation bednets were recently introduced in many African countries to overcome the challenge of insecticide resistance. These nets contain synergist piperonyl butoxide (PBO) which inhibits the activity of pyrethroid detoxifying cytochrome P450 enzymes by forming a metabolite-inhibitory complex with the enzyme. However, little is known about how African malaria vectors respond to PBO exposure at the gene transcription, biochemical and organismal level. It has been shown that in insecticide-sensitive Drosophila that PBO is capable of inducing the expression of the P450 and GST detoxification gene families. The increased production of P450 and GST enzymes by PBO exposure has the potential to increase insecticide tolerance. If this is true to malaria vectors, the impact of PBO on insecticide resistance mitigation is limited. The central objective of this continuation application is to better understand the ecology and genetics of insecticide resistance in the face of pyrethroid synergized nets introduction in the major African malaria vectors in western Kenya where we maintain selected pyrethroid resistant strains and PBO nets are being widely distributed in some counties. To achieve this goal three aims are developed. In aim 1, we will examine the impact of next-generation PBO bednets on vector bionomics and transmission reduction. Data from this will inform the effectiveness of PBO nets in transmission reduction in areas with pre-existing high pyrethroid resistance. In aim 2, we will determine the genetic basis of variations in mosquito phenotypes due to PBO nets. This aim will provide information on importance of the different mechanisms of insecticide resistance that exist in western Kenya which is critical to the development of PBO net deployment strategy. In aim 3, we will determine the response to PBO exposure at the gene transcription and biochemical level in pyrethroid resistant malaria vectors. Data from this aim can provide critical information on the genetic mechanisms and risks of PBO synergist in resistance mitigation in field malaria vector populations with high resistance. Overall, these 3 aims will inform PBO net deployment strategy, impact on transmission reduction and potential risks on its inability to mitigate resistance.