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: 9919485
• 负责人: Daniel E Neafsey
• 金额: $ 59.33万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9919485
• 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; 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 profiles; 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.

疟疾是由原生动物寄生虫在疟原虫中引起的，并由蚊子传播， 是对全球公共卫生至关重要的一种疾病。我们提出的前提是基因组 资源和技术开发有可能为新的疟疾做出巨大贡献 通过增强生物学和流行病学理解来消除努力。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，向量的理解 进化和寄生虫基因组流行病学。 目标1。为新热带疾病媒介媒介开发主要的人群基因组资源。 我们将为AN生成两个显着改进的参考基因组组件。达令，最重要的 新世界的媒介，并对An进行基于重新限制的人群基因组研究。达令和 其他新热带疟疾媒介，以识别可能的物种边界和种群结构 影响媒介能力的影响。 AIM 2。介绍疟疾寄生虫的比较种群基因组在低渗透环境中 在西非和新型方面。低转移设置中的疟疾寄生虫通常面临不同的 寄生虫在更高度流行区的挑战，包括降低的宿主免疫力，宿主内部降低 竞争，较高的治疗机会，并伴随药物的选择压力更加一致。 我们将对低转移的数千种恶性疟原虫进行全基因组测序 新型和西非的设置以识别常见和不同的人群基因组 适应和传输动态的签名 目标3。通过测序独特的寄生虫基因，可通过测序 来自Gabon的样本收集。已知疟疾寄生虫和瞬间载体相互适应 有时在非常本地的地理尺度上。我们将搜索通过 从西非加蓬收集的被感染蚊子的恶性疟原虫测序 至少有15种动态物种是三种人类疟疾寄生虫物种的载体。 目标4。定义单个感染中人类宿主和疟原虫的转录谱 肝细胞。恶性疟原虫和维瓦克斯疟原虫之间的主要生物学差异是后者的能力 在肝脏内保持代谢性休眠的催眠状态数周，数月或几年的物种 不受大多数​​药物治疗的影响。我们将研究如何在个体内调节宿主和寄生虫基因 感染的肝细胞细胞。 这项工作将通过新颖的基因组资源和方法来影响领域， 新的生物学见解和创新的分析方法。