Resistance of Malaria Parasites to Artemisinin-Based Combination Therapies

疟疾寄生虫对青蒿素类药物的抗药性 治疗方法 项目总结 非洲疟疾的控制受到不断增加的抗药性的挑战。新青蒿素- 基于联合治疗(ACT)的方案通常非常有效，最近已经 非洲几乎每个国家都将其作为简单疟疾的标准治疗方法。 然而，大量和重复使用ACTs，就像现在发生的那样，将导致强烈的选择性 对这些方案的成分产生抵抗力的压力。我们对这一机制的理解 对ACTS的抵抗是不完整的。我们建议识别抗药性的最好方法-- 在突变广泛传播之前对它们进行中介将是评估即将出现的寄生虫 治疗后，他们在长效ACT伙伴药物的选择压力下进行治疗。我们 假设治疗失败和治疗后不久出现新的感染 与ACTs相关的疟疾寄生虫中已知和未知的突变会改变 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 候选突变与临床对ACTs的反应之间的关联。我们进一步 假设增加使用ACTs将选择药物减少的寄生虫 敏感度，但也降低了适合度。为了检验这一假设，我们将搜索关联 治疗结果与药物敏感性和适合性的体外测量之间的关系。我们还将 研究引入突变的寄生虫，以测试这些变化对体外培养的影响 药物敏感性和适合性的测量。我们的具体目标将是：(1)鉴定基因类型 与非洲对ACTs反应减少有关，(2)评估分子机制 和对ACTs抗药性增加的寄生虫学后果，以及(3)表征 寄生虫基因多态对药物敏感性和适合性的具体影响。我们的研究将提供 对最重要的新抗疟药耐药机制的重要见解 养生法。它们还将具有直接的实际意义，因为它们将识别分子标记。 通过研究重点方案的耐药情况，为耐药提供“预警系统” 治疗后不久出现的寄生虫的基因类型，并提供对健康状况的洞察 阻力增加的后果。

Title: RESISTANCE OF MALARIA PARASITES TO ARTEMISININ-BASED COMBINATION THERAPIES Project summary 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 occuring, 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.