Evolutionary dynamics of zoonotic malaria

人畜共患疟疾的进化动力学

• 批准号: 10639432
• 负责人: Amy Goldberg
• 金额: $ 66.67万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-25 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10639432
• 关键词: Alouatta; Americas; Asia; Back; Binding Proteins; Blood Cells; Brazil; Case Study; Cell Surface Proteins; Cells; Clinical; Complement; Complex; Computer Models; Computing Methodologies; Demography; Development; Drug Targeting; Environment; Erythrocytes; European; Evolution; Face; Future; Gene Expression; Gene Family; Genes; Genetic; Genetic Variation; Genome; Genome Scan; Genomics; Goals; Health; Human; Human Genome; Infection; Intervention; Invaded; Life Cycle Stages; Location; Malaria; Methods; Modeling; Monkeys; Parasites; Pattern; Phylogenetic Analysis; Phylogeny; Plasmodium; Plasmodium falciparum; Plasmodium vivax; Population; Population Genetics; Predisposition; Primates; Proteins; Publishing; Recording of previous events; Reporting; Reticulocytes; Risk; Role; Route; Sampling; Sexual Reproduction; South America; South American; Southeastern Asia; Specificity; System; Techniques; Testing; Transgenic Organisms; Variant; Work; Zoonoses; burden of illness; cross-species transmission; experimental study; genetic evolution; genetic signature; genome resource; genome sequencing; genome-wide; genomic data; improved; insight; method development; nonhuman primate; novel; offspring; preference; pressure; protein structure; simulation; timeline; tool; transmission process; whole genome

Dozens of malaria species, of the genus Plasmodium, infect human and nonhuman primates worldwide. At least eight of these parasite species have moved from primate reservoirs into human populations, including historical host expansion of P. vivax and P. falciparum, the two primary malaria-causing agents in humans worldwide. As we make progress towards elimination of these common malaria parasites, emerging host switches or expansions that introduce new or rare malaria parasites into human population are an increasing barrier to global elimination. Indeed, in parts of Southeast Asia, a zoonotic malaria parasite is now the main cause of clinical malaria. The lack of genomic resources for zoonotic malaria strains, particularly from wild primates, has been a major barrier to understanding the emergence of malaria parasites and their risk for spread in human populations. Using the emerging zoonotic parasite from Brazil, P. simium, as a case study, we combine whole-genome sequencing of multiple parasite and their host populations to characterize the genetic basis of host specificity and evolution in malaria parasites. P. simium is an ideal system because it is a close relative of the well-studied P. vivax, and importantly, has recently shifted host ranges twice, first from historical human P. vivax into primates, and more recently back into humans. To interpret this new genomic data, we will combine experimental techniques with development of a whole-genome simulation framework that incorporated aspects of parasite lifecycle to better interpret neutral genetic diversity. This opens up recent developments in simulation-based inference techniques that we will use to infer the population history of South American malaria parasites, the timing of zoonoses, and identify loci under selection in multiple hosts. The function of candidate loci identified from computational approaches will then be tested with a specially- developed transgenic line expressing P. simium genes and computational modeling of protein structures from host and parasites. In sum, we combine insights from parasite genomics with complementary analyses of whole genomes from their wild primate hosts—from computational methods development to functional experiments—giving insight into the selective pressures that parasites face inside hosts and host-specific susceptibility.

疟疾属的数十种疟疾在世界各地感染人类和非人类灵长类动物。在… 这些寄生虫物种中至少有8种已经从灵长类宿主进入人类种群，包括 间日疟原虫和恶性疟原虫这两种主要的人类疟疾致病因子的历史宿主扩张 全世界。随着我们在消除这些常见疟疾寄生虫方面取得进展，新出现的宿主 将新的或罕见的疟疾寄生虫引入人类种群的开关或扩张正在增加 全球消除的障碍。事实上，在东南亚部分地区，一种人畜共患疟疾寄生虫现在是主要的 临床疟疾的病因。缺乏人畜共患疟疾菌株的基因组资源，特别是来自野生的 一直是了解疟疾寄生虫的出现及其风险的主要障碍。 在人类群体中传播。以巴西新出现的人畜共患寄生虫P.simium为例， 我们结合了多种寄生虫及其宿主种群的全基因组测序来表征 疟疾寄生虫宿主特异性和进化的遗传基础。P.simium是一个理想的系统，因为它是一种 研究充分的间日疟原虫的近亲，重要的是，最近两次改变了宿主范围，第一次是从 历史上人类间日疟原虫进入灵长类动物，最近又回到人类。来解释这种新的基因组 数据，我们将把实验技术与开发全基因组模拟框架结合起来 这包含了寄生虫生命周期的各个方面，以更好地解释中性遗传多样性。这打开了最近的 我们将用来推断南方人口历史的基于模拟的推理技术的发展 美国疟疾寄生虫，人畜共患病的时间，并确定在多个宿主中选择的基因座。这个 通过计算方法确定的候选基因座的功能将用特殊的- 拟青霉菌转基因株系的建立及其蛋白质结构的计算机模拟 寄主和寄生虫。总而言之，我们将寄生虫基因组学的见解与对 野生灵长类寄主的全基因组--从计算方法发展到功能 实验-深入了解寄生虫在宿主内部和特定于宿主的选择压力 敏感度。