Resistance of Malaria Parasites to Artemisinin-Based Combination Therapies

描述（由申请人提供）：非洲疟疾的控制受到日益增加的耐药性的挑战。新的青蒿素综合疗法一般非常有效，最近已被非洲几乎每个国家作为无并发症疟疾的标准疗法。然而，目前正在发生的大量和重复使用青蒿素综合疗法将导致对这些治疗方案的组成部分产生抗药性的强大选择压力。我们对青蒿素综合疗法耐药机制的理解是不完整的。我们认为，在耐药介导突变广泛传播之前识别它们的最佳方法是评估治疗后不久出现的寄生虫，同时它们处于长效ACT伴侣药物的选择性压力下。我们假设，治疗失败和用青蒿素综合疗法治疗后不久出现新的感染与疟疾寄生虫中已知和未知的突变有关，这些突变改变了对青蒿素伙伴药物的反应。为了验证这一假设，我们将系统地评估乌干达和布基纳法索最近和正在进行的临床试验中的寄生虫，以确定候选突变与ACT临床反应之间的关联。我们进一步假设，越来越多地使用ACTs将选择药物敏感性降低的寄生虫，但也降低了健身。为了验证这一假设，我们将寻找治疗结果与体外药物敏感性和适应性测量之间的关联。我们还将研究引入突变的寄生虫，以测试这些改变对体外药物敏感性和适应性的影响。我们的具体目标是：（1）确定与非洲对青蒿素综合疗法反应降低相关的基因型;（2）评估青蒿素综合疗法耐药性增加的分子机制和寄生虫学后果;（3）描述寄生虫多态性对药物敏感性和适应性的具体影响。我们的研究将为最重要的新抗疟疗法的耐药性机制提供重要的见解。它们还将具有直接的实际意义，因为它们将确定对关键方案的耐药性的分子标记，通过研究治疗后不久出现的寄生虫的基因型提供耐药性的“早期预警系统”，并提供对增加耐药性的健康后果的见解。公共卫生相关性：由于对旧药物的耐药性增加，新的联合疗法最近已成为治疗疟疾的标准，疟疾是世界上最大的传染病问题之一。该项目涉及研究疟疾寄生虫对新的抗疟综合疗法的抗药性机制。这些研究将具有重要的公共卫生效益，因为它们将确定简单的标志物，以在这一问题普遍存在之前确定对新药的耐药性，并将为疟疾最佳新疗法的选择提供见解。

DESCRIPTION (provided by applicant): The control of malaria in Africa is challenged by increasing drug resistance. New artemisinin based combination therapy (ACT) regimens are generally very effective, and have recently been adopted as standard therapy for uncomplicated malaria by nearly every country in Africa. However, heavy and repeated use of ACTs, as is now occurring, will lead to strong selective pressure for resistance to components of these regimens. Our understanding of mechanisms of resistance to ACTs is incomplete. We suggest that the best means of identifying resistance mediating mutations before they are widespread will be to evaluate parasites that emerge soon after therapy, while they are under the selective pressure of long-acting ACT partner drugs. We hypothesize that treatment failures and the emergence of new infections soon after treatment with ACTs will be associated with known and unknown mutations in malaria parasites that alter responses to artemisinin partner drugs. To test this hypothesis, we will systematically evaluate parasites from recent and ongoing clinical trials in Uganda and Burkina Faso to identify associations between candidate mutations and clinical responses to ACTs. We further hypothesize that increasing use of ACTs will select for parasites with decreasing drug sensitivity, but also decreased fitness. To test this hypothesis, we will search for associations between treatment outcomes and in vitro measures of drug sensitivity and fitness. We will also study parasites with introduced mutations to test the impact of these alterations on in vitro measures of drug sensitivity and fitness. Our specific aims will be (1) to identify genotypes associated with decreased responses to ACTs in Africa, (2) to assess molecular mechanisms and parasitological consequences of increasing resistance to ACTs, and (3) to characterize the specific impacts of parasite polymorphisms on drug sensitivity and fitness. Our studies will offer important insights into mechanisms of resistance to the most important new antimalarial regimens. They will also have direct practical relevance, as they will identify molecular markers of resistance to key regimens, offer an "early warning system" for resistance by studying genotypes of parasites that emerge soon after treatment, and provide insight into the fitness consequences of increasing resistance. PUBLIC HEALTH RELEVANCE: New combination therapies have recently become standard for the treatment of malaria, one of the greatest infectious disease problems in the world, due to increasing resistance to older drugs. This project involves studies of mechanisms of resistance of malaria parasites to new combination antimalarial therapies. These studies will have important public health benefits, as they will identify simple markers to identify resistance to new drugs before this problem is widespread, and they will offer insight into choices of the best new therapies for malaria.