Resistance of Malaria Parasites to Artemisinin-Based Combination Therapies in Uganda

项目摘要 在非洲控制和最终消灭疟疾的工作受到抗药性的严重挑战， 特别是对新的青蒿素联合疗法（ACT）方案的耐药性。令人担忧的迹象表明 对ACT成分的高水平耐药性正在向非洲蔓延，这是一个可怕的前景，因为大部分的 在这个大陆上发生了严重的恶性疟疾。改进了耐药性程度的表征， 抗性机制至关重要。我们假设抗疟药物敏感性是 在乌干达，对每种相关药物的耐药性都是由特定的寄生虫突变介导的， 抗药性的上升将被寄生虫的适应成本所抑制和掩盖，但持续的药物压力 会让高度适应的抗性寄生虫出现对寄生虫的先发制人的分析将是至关重要的， 在问题广泛传播之前表征耐药机制。为了验证我们的假设， 测量从乌干达患者中新鲜分离的寄生虫的药物敏感性， 不同水平的药物压力;描述这些寄生虫的遗传特征;并评估健身成本 在临床和实验室环境中的耐药性。我们认为，对新乌干达人的集中评估 分离株将使我们能够最好地描述非洲的药物敏感性和高水平耐药性的出现， 在疟疾问题最严重的地方，及时描述抗药性机制可以 最有价值的我们的研究将受益于乌干达丰富的临床研究，包括试验 研究疟疾的治疗和化学预防，监测项目从现场收集样本， 在乌干达周围，以及一项队列研究，跟踪不同疟疾风险的受试者。我们的计划也将受益于 从我们在乌干达建立的疟疾寄生虫研究实验室。我们的具体目标是：（1） 纵向表征疟原虫对ACT组分的离体敏感性，（2）表征 不同抗疟药物敏感性的遗传介质，和（3）表征不同药物的影响 疟疾寄生虫适应性的敏感性。我们的总体目标是更好地描述抗疟药物 敏感性和抗性决定因素之前，高水平的阻力变得普遍，因此，监测 这些决定因素可以指导防止抗药性蔓延的努力。

Project Summary The control and eventual elimination of malaria in Africa is seriously challenged by drug resistance, in particular resistance to new artemisinin-based combination therapy (ACT) regimens. Worrisome signs suggest that high level resistance to components of ACT is on the way to Africa, a scary prospect, since the bulk of serious falciparum malaria occurs on this continent. Improved characterization of the extent of resistance and mechanisms of resistance is of critical importance. We hypothesize that antimalarial drug sensitivity is changing in Uganda, that resistance to each relevant drug is mediated by specific parasite mutations, that the rise of resistance will be dampened and obscured by parasite fitness costs, but that continued drug pressure will allow emergence of highly fit resistant parasites. Preemptive analysis of parasites will be critical to characterizing resistance mechanisms before the problem is widespread. To test our hypotheses we will measure the drug sensitivities of parasites freshly isolated from Ugandan patients, including individuals under varied levels of drug pressure; characterize the genetic profiles of these parasites; and assess the fitness costs of resistance in both clinical and laboratory settings. We believe that focused evaluations of fresh Ugandan isolates will best equip us to characterize drug sensitivity and the emergence of high level resistance in Africa, where the malaria problem is greatest, and where timely characterization of resistance mechanisms can be most valuable. Our studies will benefit from access to a wealth of clinical studies in Uganda, including trials studying the treatment and chemoprevention of malaria, surveillance programs collecting samples from sites around Uganda, and a cohort study following subjects at varied risks of malaria. Our program will also benefit from our established laboratories for the study of malaria parasites in Uganda. Our specific aims will be: (1) to longitudinally characterize the ex vivo sensitivity of malaria parasites to ACT components, (2) to characterize genetic mediators of varied antimalarial drug sensitivity, and (3) to characterize impacts of varied drug sensitivity on the fitness of malaria parasites. Our overall goal is to better characterize antimalarial drug sensitivity and resistance determinants before high level resistance becomes widespread, so that monitoring of these determinants can guide efforts to circumvent the spread of resistance.