Project 4 Genomic and transcriptomic interactions between malaria parasites, their mosquito vectors, and human hosts at the scale of continents, villages, and single cells

疟疾，由疟原虫属原生动物寄生虫引起，由按蚊传播， 是一种对全球公共卫生至关重要的疾病。我们提议的前提是基因组 资源和技术发展有可能极大地促进疟疾死灰复燃 通过加强对生物学和流行病学的了解来消除努力。所描述的工作 这项研究将促进我们对寄生虫/媒介相互作用、寄生虫/人类相互作用、媒介 进化论和寄生虫基因组流行病学。 目的1.开发新热带按蚊媒的主要种群基因组资源。 我们将为AN生成两个显著改进的参考基因组组件。亲爱的，最重要的 新大陆的媒介，并进行基于重新测序的按蚊种群基因组研究。达林吉和 其他新热带疟疾媒介，以确定神秘的物种边界和种群结构 影响向量能力的特征。 目的2.描述低传播环境中疟疾寄生虫的比较种群基因组学 在西非和新热带地区。低传播环境中的疟疾寄生虫通常面临不同的 来自更高流行区寄生虫的挑战，包括宿主免疫力下降、宿主内减少 竞争，更高的治疗机会，以及随之而来的来自药物的更持续的选择压力。 我们将对来自低传播率的数千种恶性疟原虫进行全基因组测序 在新热带和西非确定共同的和不同的种群基因组的环境 适应和传播动力学的特征 目的3.通过测序确定与蚊子媒介相互作用的寄生虫基因 从加蓬采集样本。已知疟疾寄生虫和按蚊媒介相互适应， 有时是在非常局部的地理范围内。我们将通过以下方式寻找调节这种适应的寄生虫基因 从西非加蓬采集的受感染蚊子中测定恶性疟原虫的序列 至少有15种按蚊作为三种人类疟疾寄生虫的媒介。 目的4.确定人类宿主和疟原虫在单一感染中的转录图谱 肝细胞。恶性疟原虫和间日疟原虫的关键生物学区别在于后者的能力。 在肝脏内保持新陈代谢休眠的催眠体状态数周、数月或数年的物种， 不受大多数药物治疗的影响。我们将研究寄主和寄生虫基因在个体内是如何调控的 感染的肝细胞。 这项工作将通过产生新的基因组资源和方法来影响该领域， 新的生物学见解和创新的分析方法。

Malaria, caused by protozoan parasites in the genus Plasmodium and transmitted by Anopheles mosquitoes, is a disease of critical importance to global public health. The premise of our proposal is that genomic resources and technology development have the potential to greatly contribute to the renewed malaria elimination effort through enhanced biological and epidemiological understanding. The work described in this study will advance our understanding of parasite/vector interactions, parasite/human interactions, vector evolution, and parasite genomic epidemiology. AIM 1. Develop a major population genomic resource for Neotropical anopheline malaria vectors. We will generate two significantly improved reference genome assemblies for An. darlingi, the most important vector in the New World, and perform resequencing-based population genomic studies of An. darlingi and other neotropical malaria vectors to identify cryptic species boundaries and population structure that could impact traits contributing to vectorial capacity. AIM 2. Profile the comparative population genomics of malaria parasites in low-transmission settings in West Africa and the Neotropics. Malaria parasites in low-transmission settings typically face distinct challenges from parasites in more highly endemic zones, including reduced host immunity, reduced intra-host competition, higher access to treatment, and concomitantly more consistent selection pressure from drugs. We will perform whole genome sequencing of thousands of P. falciparum parasites from low-transmission settings in the Neotropics and West Africa to identify common as well as distinct population genomic signatures of adaptation and transmission dynamics AIM 3. Identify parasite genes that mediate interactions with mosquito vectors by sequencing a unique sample collection from Gabon. Malaria parasites and anopheline vectors are known to adapt to each other, sometimes on very local geographic scales. We will search for parasite loci that mediate this adaptation by sequencing Plasmodium falciparum from infected mosquitoes collected in Gabon, West Africa, a region where at least 15 anopheline species serve as vectors for three human malaria parasite species. AIM 4. Define the transcriptional profile of the human host and Plasmodium parasites in single infected hepatocytes. The key biological difference between P. falciparum and P. vivax is the capacity of the latter species to remain in a metabolically dormant hypnozoite state within the liver for weeks, months, or years, impervious to most drug treatments. We will study how host and parasite genes are regulated within individual infected hepatocyte cells. This work will influence the field through the generation of novel genomic resources and methods, new biological insights, and innovative analytical methods.