Genomics of Mosquito Resistance to Plasmodium

描述（由申请人提供）：该项目自成立以来，首次系统地研究了自然界中蚊子对人类疟疾寄生虫的免疫和抗性机制。了解这些相互作用的生物学可以允许开发新的策略来抑制寄生虫传播。在本项目期间，我们对西非马里的主要人类疟疾病媒冈比亚按蚊进行了实地遗传调查。这项工作首次在A.冈比亚，减少恶性疟原虫的自然传播。这个集群被命名为A. gambiae，包含调节A. falciparum感染的主要基因组控制区。冈比亚人口。疟原虫抗性等位基因在PRI中被发现在自然媒介人群中的频率很高。我们在PRI区域确定并鉴定了一个名为APL1的候选基因，该基因可以保护蚊子免受啮齿类疟疾寄生虫伯氏疟原虫的感染。在这里，我们提出了新的综合目标，直接建立在以前的工作中提取的PRI性状从自然到实验室，并研究疟原虫抗性的功能机制控制的等位基因的PRI。我们将：1）使用无偏见的全基因组扫描调查，从功能上确定蚊子对疟原虫的抗性机制的疟原虫种属特异性。2)从天然恶性疟原虫抗性岛（PRI）中选择抗疟原虫和易感疟原虫变异体的纯系。3)从功能上剖析由PRI控制的自然疟原虫抗性的潜在致病基因组、细胞和生理机制。拟议的更新项目将是第一个功能性研究的机制，直接确定在蚊子现场人口，赋予抵抗人类疟疾寄生虫。我们将全面确定稳健伯氏疟原虫作为恶性疟原虫感染蚊子的实验室模型的有效性，我们将针对天然PRI性状创建纯抗性和易感蚊子品系，并且我们将在功能上比较两个品系中寄生虫的命运，并使用目标1.相关性中确定的适当寄生虫模型确定其在抗性蚊子中的消除机制。有可能制定新的疟疾控制战略，重点放在蚊子媒介上。了解影响病媒蚊子传播疟疾的遗传机制将有助于制定这种基于病媒的控制战略。

DESCRIPTION (provided by applicant): Since its inception, this project has comprised the first systematic examination of mechanisms of mosquito immunity and resistance to human malaria parasites in nature. Understanding the biology of these interactions could permit development of novel strategies to inhibit parasite transmission. In the current project period, we carried out a field-based genetic survey of the major human malaria vector, Anopheles gambiae, in Mali, West Africa. This work for the first time identified a significant cluster of genetic loci in A. gambiae that reduce the natural transmission of P. falciparum. This cluster, named the Plasmodium- resistance island (PRI) of A. gambiae, comprises the major genomic control region for regulation of P. falciparum infection in the A. gambiae population. Plasmodium resistance alleles in the PRI are found at high frequency in the natural vector population. We identified and characterized a candidate gene in the PRI region, called APL1, which protects mosquitoes against infection by the rodent malaria parasite, P. berghei. Here, we present new integrated Aims that build directly upon the previous work to extract the PRI trait from nature into the laboratory, and study the functional mechanisms of malaria parasite resistance controlled by alleles of the PRI. We will: 1) Functionally determine Plasmodium species-specificity of mosquito resistance mechanisms against malaria parasites using an unbiased genome-wide scanning survey. 2) Select pure lines of Plasmodium-resistant and susceptible variants from the natural P. falciparum resistance island (PRI). 3) Functionally dissect the underlying causative genomic, cellular and physiological mechanism(s) of natural Plasmodium resistance controlled by the PRI. The proposed renewal project will be the first functional study of mechanisms identified directly in a mosquito field population that confer resistance to human malaria parasites. We will comprehensively determine the validity of the robust P. berghei as a laboratory model for P. falciparum infection of mosquitoes, we will create pure resistant and susceptible mosquito lines for the natural PRI trait, and we will functionally compare the fate of parasites in the two lines and determine the mechanism of their elimination in the resistant mosquitoes, using the appropriate parasite model as determined in Aim 1.Relevance. It may be possible to develop new strategies for malaria control focusing on the mosquito vector. Knowledge of the genetic mechanisms that affect transmission of malaria by vector mosquitoes would aid in the development of such vector-based control strategies.