Evolution of Plasmodium vivax and Asian Macaque Malarias

间日疟原虫和亚洲猕猴疟疾的进化

• 批准号: 7918996
• 负责人: Ananias Alberto Escalante
• 金额: $ 30.37万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7918996
• 关键词: Africa; Africa South of the Sahara; Area; Asia; Asians; Binding; Central America; Cercopithecidae; Complex; Data; Developing Countries; Development; Erythrocytes; Event; Evolution; Frequencies; Genes; Genetic Polymorphism; Genetic Variation; Homo; Human; Intervention; Investigation; Life Cycle Stages; Link; Macaca; Maintenance; Malaria; Malaria Vaccines; Measures; Methods; Molecular; Morbidity - disease rate; Mutation; Natural Selections; Nuclear; Parasites; Pattern; Pharmaceutical Preparations; Phylogenetic Analysis; Plasmodium; Plasmodium falciparum; Plasmodium vivax; Population; Population Genetics; Population Growth; Poverty; Process; Proteins; Public Health; Radiation; Recording of previous events; Reporting; Role; Sampling; Sister; South America; Southeastern Asia; Specificity; Structure; System; Taxon; Testing; Vaccines; Variant; comparative; disorder risk; improved; mitochondrial genome; mortality; nonhuman primate; novel strategies; public health relevance; simulation; southeast Asian; transmission process

DESCRIPTION (provided by applicant): PLASMODIUM VIVAX is the most prevalent human malarial parasite in several areas of Asia and South-Central America. Phylogenetic studies have shown that P. vivax and other Plasmodium spp. currently found in Southeast Asian macaques are part of a monophyletic group from which P. vivax originated as a human parasite as a result of a host switch. The proposed investigation seeks to understand the evolutionary history of P. vivax together with its known sister taxa in Southeast Asian macaques. Understanding the evolutionary history of macaque malarias is important because some of these parasites can infect humans. Overall, the proposed investigation aims to understand the role of positive selection in the evolution of proteins expressed during erythrocyte invasion in P. vivax and related species. This is a critical step in the parasite life cycle. Several of these proteins are considered targets for malaria vaccines. Spurious evidence of positive selection, however, could result from demographic processes (such as population growth and population structure). Thus we propose to assess the demographic histories of P. vivax and macaque Plasmodium spp., using extensive geographic sampling to understand the evolution of putative adaptive variation. This proposal includes two interrelated aims: Specific aim 1: To investigate the demographic histories of P. vivax and related macaque malarial parasite populations. This investigation will allow us to test the following hypotheses: a) P. vivax originated in Asia as a H. sapiens parasite and has a complex demographic history that includes population expansions outside Asia; b) although host switches have been reported in Plasmodium spp., we hypothesize that within-host-species transmission has been be favored over between-host-species transmission. Thus, we expect to find host-specific lineages in multi-host Plasmodium associated with Southeast Asian macaques. Such lineages will provide a suitable framework to estimate the mutation rates at neutral loci, and by so doing, we can improve our understanding of the recent demographic history of P. vivax. Specific aim 2: To investigate the mode of evolution, extent, and maintenance of genetic diversity in erythrocyte invasion proteins (EIP) in P. vivax and related species. We hypothesize that among the EIP, divergence due to natural selection in the P. vivax branch will be observed in proteins which reflect molecular adaptations of this parasite to Homo after it switched from Cercopithecidae hosts. Second, we will sequence loci encoding EIP proteins in extant populations of P. vivax and related macaque malarial parasites. We will explore their observed polymorphism by using comparative and coalescent simulations approaches. We will test the hypothesis that putative adaptive polymorphisms will be observed in P. vivax EIP, especially at those proteins known to bind the erythrocyte. PUBLIC HEALTH RELEVANCE Although P. vivax is the most prevalent malarial parasite outside Sub-Saharan Africa, there is little information about its genetic diversity. Such information is essential for developing and deploying control measures such as vaccines and drugs. This investigation will also provide information about the distribution, frequency, and host-specificity of macaque malarias. Since these parasites have been found to infect humans in Southeast Asia, understanding their distribution and genetic diversity will be an important first step in assessing the disease risk for humans.

描述（由申请人提供）：疟原虫是亚洲和美国中南部几个地区最普遍的人类疟原虫。系统发育研究表明，假单疟原虫和其他疟原虫属。目前在东南亚猕猴中发现的是单属群体的一部分，该群体是宿主开关导致的。拟议的调查旨在了解Vivax的进化史以及其在东南亚猕猴中的知名姊妹分类单元。了解猕猴的进化史很重要，因为其中一些寄生虫可以感染人类。总体而言，拟议的调查旨在了解阳性选择在体内且相关物种中红细胞侵袭期间表达的蛋白质进化中的作用。这是寄生虫生命周期中的关键步骤。这些蛋白质中的几种被认为是疟疾疫苗的靶标。然而，阳性选择的虚假证据可能是由于人口过程（例如人口增长和人口结构）引起的。因此，我们建议使用广泛的地理抽样来评估疟原虫和猕猴的人口统计学历史，以了解推定的适应性变化的演变。该提案包括两个相互关联的目的：特定目的1：研究Vivax和相关猕猴疟原虫种群的人口统计学历史。这项调查将使我们能够检验以下假设：a）Vivax起源于亚洲，是H. sapiens寄生虫，并且具有复杂的人口统计历史，其中包括亚洲以外的人口扩展； b）尽管已经在疟原虫属中报道了宿主开关，但我们假设宿主内物种的传播受到托管之间的传播的青睐。因此，我们期望在与东南亚猕猴相关的多宿主疟原虫中找到宿主特异性谱系。这样的谱系将提供一个合适的框架来估计中性基因座的突变率，通过这样做，我们可以提高对Vivax近期人口统计学历史的理解。具体目的2：研究在拟南芥和相关物种中红细胞侵袭蛋白（EIP）中遗传多样性的进化，程度和维持方式。我们假设在EIP中，将在蛋白质中观察到由于蛋白质的自然选择而导致的差异，这反映了该寄生虫从Cercopithecidae宿主切换后对HOMO的分子适应。其次，我们将在维瓦克斯和相关的猕猴疟原虫现有种群中编码EIP蛋白的编码基因座对基因座进行测序。我们将通过使用比较和融合模拟方法来探索他们观察到的多态性。我们将检验以下假设，即在Vivax EIP中将观察到推定的自适应多态性，尤其是在已知结合红细胞的蛋白质上。公共卫生的相关性尽管维瓦克斯是撒哈拉以南非洲以外的最普遍的疟原虫，但关于其遗传多样性的信息很少。此类信息对于制定和部署控制措施，例如疫苗和药物至关重要。这项研究还将提供有关猕猴疟疾的分布，频率和宿主特异性的信息。由于已经发现这些寄生虫在东南亚感染了人类，因此了解其分布和遗传多样性将是评估人类疾病风险的重要第一步。