A Global Comparative Study of the Evolution of Antimalarial Drug Resistance

抗疟药物耐药性演变的全球比较研究

基本信息

批准号：
7446470
负责人：
Ananias Alberto Escalante
金额：
$ 36.28万
依托单位：
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-05 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7446470
关键词：
Accounting Affect Africa Africa South of the Sahara Alleles Anti-malarial drug resistance Antimalarials Area Asia Cambodia Cessation of life Characteristics Chloroquine Chloroquine resistance Clinical Combined Modality Therapy Comparative Study Complex Condition Country Demography Disease Drug resistance Drug-sensitive Ecology Evolution Falciparum Malaria Frequencies Genes Genetic Genetic Anticipation Genetic Recombination Genetic Variation Health Knowledge Life Link Linkage Disequilibrium Maintenance Malaria Malawi Microsatellite Repeats Mitochondrial DNA Modeling Molecular Mutation Outcome Parasites Pattern Pharmaceutical Preparations Plasmodium falciparum Point Mutation Policies Population Population Genetics Population Sizes Public Health Pyrimethamine Pyrimethamine-Sulfadoxine Recording of previous events Relative (related person)Resistance Rotation Site South America Southeastern Asia Structure Sulfadoxine Sulfadoxine-pyrimethamine resistance Testing Textbooks Venezuela base comparative cost drug sensitivity fitness interest mathematical model mutant pressure tool transmission process

项目摘要

DESCRIPTION (provided by applicant): Malaria causes more than 500 million clinical cases and one-million deaths per year. Plasmodium falciparum is responsible for most malaria-related deaths. Anti-malarial drugs save millions of lives every year; however, the evolution of drug resistance in P. falciparum is a major global health threat. We will investigate the dynamics of mutations associated with chloroquine and sulfadoxine-pyrimethamine (SP) resistance across multiple P. falciparum populations with different epidemiological characteristics and demographic histories. Overall, this proposal aims to generate new empirical and theoretical knowledge about how advantageous mutations can sweep through large structured populations with complex demographic histories and then decline when the selective pressure changes. By comparing several populations, we will provide information regarding which types of populations are most prone to the emergence of drug resistance or to the reemergence of drug sensitivity and will provide theoretical tools to evaluate potential drug policies (e.g. combination therapy or drug rotation) under scenarios likely to be encountered in different endemic areas. (1) We will use microsatellites linked to drug resistance alleles and neutral loci to estimate the relative fitness of mutations associated with resistance in the context of the parasite population demography (e.g. local population structure, effective population size, and amount of recombination) during single and/or multiple selective sweeps. We will (1A) estimate the demographic history of P. falciparum populations using neutral markers from seven endemic areas: two from South America, four from Africa, and one from Asia; (1B) assess how the demographic history of these populations affects the fitness of mutations associated with SP and chloroquine resistance sweeping simultaneously in a population in the presence of drug pressure; 1C) estimate the fitness cost of resistance in the absence of drug pressure. (2) We will develop mathematical models that predict/assess the dynamics of resistant and sensitive alleles taking into account their relative fitness, the disease ecology, and the demographic history of the parasite population. 2A) We will validate them by (i) predicting patterns of selective sweeps and linkage disequilibrium on loci under selection by antimalarial drugs in specific populations, (ii) testing the hypothesis that drug-resistance is more likely to emerge under low transmission conditions like those observed in South America and Southeast Asia, and (iii) testing the hypothesis that in the absence of drug pressure, drug sensitivity is more likely to re-emerge under high transmission conditions like those in Africa.

描述（由申请人提供）：疟疾每年造成超过5亿个临床病例和100万人死亡。恶性疟原虫负责大多数与疟疾相关的死亡。抗菌药物每年挽救数百万生命；但是，恶性疟原虫耐药性的进化是全球主要的健康威胁。我们将研究与具有不同流行病学特征和人口统计学历史不同的多个恶性疟原虫种群中氯喹和磺胺毒素 - 羟胺（SP）抗性相关的突变动力学。总体而言，该提案旨在产生有关有利突变如何扫除具有复杂人口统计学历史的大型结构化种群的新经验和理论知识，然后在选择性压力变化时会下降。通过比较几个人群，我们将提供有关哪些类型种群最容易出现耐药性或药物敏感性的升高性的信息，并将提供理论工具，以评估在不同地方性地区可能遇到的情况下可能遇到的潜在药物政策（例如联合治疗或药物旋转）。（1）我们将使用与耐药性等位基因和中性基因座相关的微卫星来估计在寄生虫种群人口统计的背景下与抗药性相关的相对适应性（例如，在单次和/或多个选择性扫描中，寄生虫种群人口统计学（例如，有效的人口结构，有效的种群大小和重组量）。我们（1a）将使用来自七个流行地区的中性标记：南美的两个，四个来自非洲，一个来自亚洲的中性标记，估计恶性疟原虫种群的人口统计学历史；（1b）评估这些人群的人口历史如何影响与SP和氯喹抗性相关的突变的适应性，并在药物压力的存在下同时扫除了人群； 1C）在没有药物压力的情况下估计抵抗力的适应性成本。（2）我们将开发数学模型，以预测/评估抗性和敏感等位基因的动态，并考虑其相对适应性，疾病生态学和寄生虫种群的人口统计历史。 2A) We will validate them by (i) predicting patterns of selective sweeps and linkage disequilibrium on loci under selection by antimalarial drugs in specific populations, (ii) testing the hypothesis that drug-resistance is more likely to emerge under low transmission conditions like those observed in South America and Southeast Asia, and (iii) testing the hypothesis that in the absence of drug pressure, drug sensitivity is more likely to像非洲这样的高传输条件下重新出现。