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

• 批准号: 8069180
• 负责人: Ananias Alberto Escalante
• 金额: $ 34.96万
• 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: 2008-05-05 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8069180
• 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; Country; Demography; Disease; Drug resistance; Drug-sensitive; Ecology; Epidemiology; Evolution; Falciparum Malaria; Frequencies; Genes; Genetic; Genetic Anticipation; Genetic Recombination; Genetic Variation; Knowledge; 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-Sulfadoxine; Recording of previous events; Relative (related person); Resistance; Rotation; Site; South America; Southeastern Asia; Structure; Sulfadoxine-pyrimethamine resistance; Testing; Textbooks; Venezuela; base; comparative; cost; drug sensitivity; effective therapy; fitness; global health; interest; mathematical model; mutant; pressure; resistance allele; tool; transmission process

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）：疟疾每年导致超过 5 亿临床病例和 100 万人死亡。恶性疟原虫是大多数与疟疾相关的死亡的原因。抗疟疾药物每年挽救数百万人的生命；然而，恶性疟原虫耐药性的演变是全球健康的主要威胁。我们将研究具有不同流行病学特征和人口统计史的多个恶性疟原虫种群中与氯喹和磺胺多辛-乙胺嘧啶 (SP) 耐药性相关的突变动态。总体而言，该提案旨在产生新的经验和理论知识，了解有利的突变如何席卷具有复杂人口历史的大型结构化人群，然后在选择压力发生变化时下降。通过比较几个人群，我们将提供有关哪些类型的人群最容易出现耐药性或重新出现药物敏感性的信息，并将提供理论工具来评估情景下潜在的药物政策（例如联合治疗或药物轮换）可能在不同的流行地区遇到。 (1) 我们将使用与耐药等位基因和中性位点相关的微卫星来估计单次耐药期间寄生虫种群人口统计学背景下与耐药相关的突变的相对适应性（例如当地种群结构、有效种群规模和重组量）。和/或多次选择性扫描。我们将 (1A) 使用来自七个流行地区的中性标记估计恶性疟原虫种群的人口历史：两个来自南美洲，四个来自非洲，一个来自亚洲； (1B) 评估这些人群的人口统计史如何影响在存在药物压力的人群中同时发生的 SP 和氯喹耐药性相关突变的适应性； 1C) 估计在没有药物压力的情况下抵抗的适应成本。 (2) 我们将开发数学模型来预测/评估抗性和敏感等位基因的动态，同时考虑它们的相对适应性、疾病生态学和寄生虫种群的人口统计历史。 2A) 我们将通过以下方式验证它们：(i) 预测特定人群中抗疟药物选择的基因座上的选择性扫描和连锁不平衡模式，(ii) 检验在低传播条件下更有可能出现耐药性的假设在南美和东南亚观察到的情况，以及（iii）检验以下假设：在没有药物压力的情况下，药物敏感性更有可能在非洲等高传播条件下重新出现。

项目成果

Tracking origins and spread of sulfadoxine-resistant Plasmodium falciparum dhps alleles in Thailand.

追踪泰国耐磺胺多辛的恶性疟原虫 dhps 等位基因的起源和传播。

• 发表时间: 2011-01
• 影响因子: 4.9
• 作者: Alam, Md Tauqeer;Vinayak, Sumiti;Congpuong, Kanungnit;Wongsrichanalai, Chansuda;Satimai, Wichai;Slutsker, Laurence;Escalante, Ananias A;Barnwell, John W;Udhayakumar, Venkatachalam
• 通讯作者: Udhayakumar, Venkatachalam

Hitchhiking effect of a beneficial mutation spreading in a subdivided population.

有益突变在细分群体中传播的搭便车效应。

• 发表时间: 2011-09
• 影响因子: 3.3
• 作者: Kim, Yuseob;Maruki, Takahiro
• 通讯作者: Maruki, Takahiro

Fitness components and natural selection: why are there different patterns on the emergence of drug resistance in Plasmodium falciparum and Plasmodium vivax?

健身成分与自然选择：为什么恶性疟原虫和间日疟原虫耐药性的出现有不同的模式？

• 发表时间: 2013
• 影响因子: 3
• 作者: Schneider, Kristan A;Escalante, Ananias A
• 通讯作者: Escalante, Ananias A

The dynamics of mutations associated with anti-malarial drug resistance in Plasmodium falciparum.

与恶性疟原虫抗疟疾耐药性相关的突变动态。

• 发表时间: 2009-12
• 影响因子: 9.6
• 作者: Escalante, Ananias A;Smith, David L;Kim, Yuseob
• 通讯作者: Kim, Yuseob

pfmdr1 amplification and fixation of pfcrt chloroquine resistance alleles in Plasmodium falciparum in Venezuela.

委内瑞拉恶性疟原虫中 pfcrt 氯喹抗性等位基因的 pfmdr1 扩增和固定。

• 发表时间: 2010-04
• 影响因子: 4.9
• 作者: Griffing, Sean;Syphard, Luke;Sridaran, Sankar;McCollum, Andrea M;Mixson;Vinayak, Sumiti;Villegas, Leopoldo;Barnwell, John W;Escalante, Ananias A;Udhayakumar, Venkatachalam
• 通讯作者: Udhayakumar, Venkatachalam