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

项目 4 疟疾寄生虫、其蚊媒和人类宿主之间在大陆、村庄和单细胞范围内的基因组和转录组相互作用

• 批准号: 10163680
• 负责人: Daniel E Neafsey
• 金额: $ 60.81万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-10 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163680
• 关键词: Africa; Anopheles Genus; Biological; Cells; Cessation of life; Clinical; Collaborations; Collection; Communicable Diseases; Culicidae; DNA Resequencing; Data Set; Developing Countries; Disease; Economics; Epidemiology; Evolution; Face; Gabon; Gene Expression Profile; Generations; Genes; Genetic Transcription; Genomic Centers for Infectious Diseases; Genomics; Geography; Health Services Accessibility; Hepatocyte; Human; Immunity; In Vitro; Individual; Intervention; Liver; Malaria; Measures; Mediating; Metabolic; Methods; Morbidity - disease rate; Parasite Control; Parasites; Parasitic Diseases; Pharmaceutical Preparations; Pharmacotherapy; Plasmodium; Plasmodium falciparum; Plasmodium vivax; Population; Population Sizes; Public Health; Resource Development; Resources; Signal Transduction; Structure; System; Technology; Vectorial capacity; Work; World Health Organization; analytical method; combat; commune; comparative; effective therapy; genome sequencing; genomic data; genomic epidemiology; genomic locus; genomic signature; improved; innovation; insight; liver infection; malaria infection; mortality; novel; population based; practical application; pressure; programs; reference genome; response; sample collection; technology development; trait; transcriptomics; transmission process; vector; vector control; vector mosquito; whole genome

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.

疟疾，由疟原虫属原生动物寄生虫引起并由按蚊传播， 是一种对全球公共卫生至关重要的疾病。我们建议的前提是基因组 资源和技术开发有可能极大地促进疟疾的复发 通过加强生物学和流行病学的了解来努力消除病毒。所描述的工作 这项研究将增进我们对寄生虫/病媒相互作用、寄生虫/人类相互作用、病媒 进化和寄生虫基因组流行病学。 目标 1. 开发新热带按蚊疟疾媒介的主要种群基因组资源。 我们将为 An 生成两个显着改进的参考基因组组件。达林吉，最重要的 载体，并进行基于重测序的群体基因组研究。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，可以 有助于矢量能力的影响特征。 目标 2. 分析低传播环境中疟疾寄生虫的比较群体基因组学 分布于西非和新热带地区。低传播环境中的疟疾寄生虫通常面临着不同的挑战 来自高流行区寄生虫的挑战，包括宿主免疫力降低、宿主内感染减少 竞争、更高的治疗机会以及随之而来的更一致的药物选择压力。 我们将对数千种低传播性恶性疟原虫进行全基因组测序 新热带地区和西非的环境，以确定共同和独特的群体基因组 适应和传播动力学的特征 目标 3. 通过对独特的序列进行测序来识别介导与蚊子媒介相互作用的寄生虫基因 来自加蓬的样本采集。众所周知，疟疾寄生虫和按蚊媒介能够相互适应， 有时在非常局部的地理范围内。我们将通过以下方式寻找介导这种适应的寄生虫位点 对西非加蓬收集的受感染蚊子中的恶性疟原虫进行测序，该地区 至少有 15 种按蚊是三种人类疟疾寄生虫的媒介。 目标 4. 确定单个感染者中人类宿主和疟原虫寄生虫的转录谱 肝细胞。恶性疟原虫和间日疟原虫之间的主要生物学差异在于后者的能力 物种在肝脏内保持代谢休眠催眠状态数周、数月或数年， 不受大多数​​药物治疗的影响。我们将研究宿主和寄生虫基因如何在个体内受到调节 感染的肝细胞。 这项工作将通过产生新颖的基因组资源和方法影响该领域， 新的生物学见解和创新的分析方法。