Genomics of Mosquito Resistance to Plasmodium

描述（由申请人提供）：本项目自成立以来，首次系统地研究了蚊子对自然界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原理可以开发出抑制寄生虫传播的新策略。在本项目期间，我们在西非马里对主要的人类疟疾媒介冈比亚按蚊进行了实地遗传调查。这项工作首次在冈比亚疟蚊中发现了减少恶性疟原虫自然传播的重要遗传位点群。这一群被命名为冈比亚疟蚊的疟原虫抗性岛（PRI），是冈比亚疟蚊种群中恶性疟原虫感染调控的主要基因组控制区。PRI中的疟原虫抗性等位基因在自然媒介种群中发现频率很高。我们在PRI区发现并鉴定了一个候选基因，称为APL1，它可以保护蚊子免受啮齿动物疟原虫伯氏疟原虫的感染。本文在前人研究的基础上，提出了新的综合目标，从自然界提取PRI性状到实验室，研究PRI等位基因控制的疟原虫抗性的功能机制。我们将：1)利用无偏倚的全基因组扫描调查，从功能上确定蚊子对疟原虫抗性机制的疟原虫物种特异性。2)从天然恶性疟原虫耐药岛（PRI）中选择疟原虫耐药和敏感变异纯种。3)功能性剖析由PRI控制的疟原虫天然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直接在蚊子种群中确定的赋予人类疟疾寄生虫抗性的机制的功能性研究。我们将全面确定健壮的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，我们将为天然PRI性状创建纯抗性和易感蚊子系，我们将使用Aim 1.Relevance中确定的适当寄生虫模型，对两种疟原虫的命运进行功能比较，并确定它们在抗性蚊子中的消除机制。有可能制定以蚊子媒介为重点的疟疾控制新战略。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.