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: 10610397
• 负责人: Daniel E Neafsey
• 金额: $ 62.33万
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10610397
• 关键词: Project; Genomic; transcriptomic; interactions; between

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.

疟疾由疟原虫属的原生动物寄生虫引起，由按蚊传播， 是对全球公共卫生至关重要的疾病。我们的建议的前提是， 资源和技术的发展有可能大大有助于疟疾的重新流行， 通过加强对生物学和流行病学的了解，努力消除疟疾。描述的工作 在这项研究中，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 进化和寄生虫基因组流行病学。 AIM 1.开发新热带区按蚊疟疾病媒的主要人群基因组资源。 我们将为An产生两个显著改进的参考基因组组装体。亲爱的，最重要的 载体在新的世界，并进行基于重测序的人口基因组研究的一个。达林吉和 其他新热带疟疾病媒，以确定神秘的物种边界和人口结构， 影响向量能力的性状。 AIM 2.描述低传播环境中疟疾寄生虫的比较群体基因组学 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风险， 在更高度流行的地区，寄生虫的挑战，包括宿主免疫力下降，宿主内免疫力下降， 竞争，更容易获得治疗，以及随之而来的来自药物的更一致的选择压力。 我们将对来自低传播的数千种恶性疟原虫进行全基因组测序， 在新热带地区和西非的设置，以确定共同的，以及不同的人口基因组 适应和传播动力学特征 AIM 3.通过对一个独特的DNA序列进行测序， 从加蓬采集样本。众所周知，疟疾寄生虫和按蚊载体会相互适应， 有时是在非常局部的地理范围内。我们将寻找介导这种适应的寄生虫基因座， 从西非加蓬收集的受感染蚊子中对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。 AIM 4.确定人类宿主和疟原虫单次感染中的转录谱 肝细胞恶性疟原虫和间日疟原虫之间的关键生物学差异是后者的能力 物种在肝脏内保持代谢休眠催眠子状态数周、数月或数年， 对大多数药物治疗无效我们将研究宿主和寄生虫的基因是如何在个体内调节的， 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。