Resistance of Malaria Parasites to Artemisinin-Based Combination Therapies

描述(申请人提供)：非洲疟疾的控制受到不断增加的抗药性的挑战。新的基于青蒿素的联合疗法(ACT)通常非常有效，最近几乎每个非洲国家都将其作为简单疟疾的标准疗法。然而，就像现在发生的那样，大量和重复使用ACTs将导致对这些方案的组成部分产生强大的选择压力。我们对ACTs抵抗机制的理解是不完整的。我们建议，在耐药性中介突变广泛传播之前，识别它们的最好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伙伴药物的选择压力下。我们假设，治疗失败和在使用ACTS治疗后不久出现新的感染将与疟疾寄生虫的已知和未知突变有关，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，以确定候选突变和对ACTs的临床反应之间的关联。我们进一步假设，增加使用ACTs将选择对药物敏感性降低的寄生虫，但也会降低适应性。为了验证这一假设，我们将寻找治疗结果与药物敏感性和适合性的体外测量之间的联系。我们还将研究引入突变的寄生虫，以测试这些变化对药物敏感性和适应性的体外测量的影响。我们的具体目标将是(1)确定与非洲对ACTs反应降低相关的基因类型，(2)评估对ACTs耐药性增加的分子机制和寄生虫学后果，以及(3)表征寄生虫多态对药物敏感性和适合性的具体影响。我们的研究将为最重要的新抗疟疾方案的耐药机制提供重要的见解。它们还将具有直接的实际意义，因为它们将识别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类型来提供耐药性的“早期预警系统”，并提供对增加耐药性的适合性后果的洞察。与公共卫生相关：由于对旧药的耐药性增加，新的联合疗法最近已成为治疗疟疾的标准疗法，疟疾是世界上最大的传染病问题之一。该项目涉及疟疾寄生虫对新的联合抗疟疾疗法的抗药性机制的研究。这些研究将对公众健康产生重要的益处，因为它们将识别简单的标记物，在这个问题普遍存在之前识别对新药的耐药性，并将为疟疾最佳新疗法的选择提供洞察力。

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.