Resistance of Malaria Parasites to Artemisinin-Based Therapies

 描述(申请人提供)：非洲疟疾的控制和最终消灭受到抗药性的严重挑战，特别是对新的青蒿素联合疗法(ACT)方案的抗药性。令人担忧的迹象表明，对ACT成分的高度抗药性正在向非洲蔓延，这是一个可怕的前景，因为大部分严重的恶性疟疾发生在非洲大陆。改善耐药程度和耐药机制的特征至关重要。我们假设，乌干达的抗疟疾药物耐药性正在增加，耐药性的上升将受到寄生虫适应成本的抑制和掩盖，但持续的药物压力将允许耐药寄生虫的出现，这些寄生虫保持足够的适应能力，很容易传播。对寄生虫的先发制人的分析将是在该问题广泛传播之前表征抗药性机制的关键。为了验证我们的假设，我们将监测在不同药物压力水平下从乌干达患者身上分离的疟疾寄生虫的药物敏感性；表征这些寄生虫的基因图谱；评估临床和实验室环境中耐药性的适合性、毒力和可传播性成本；以及表征选定的临床或实验室中的高水平耐药性。我们认为，对乌干达新分离株的重点评估将使我们最有能力确定非洲出现高水平耐药性的特征，因为非洲的疟疾问题最严重，及时确定耐药性机制可能是最有价值的。我们的研究将受益于在乌干达进行的大量临床试验，研究疟疾的治疗和化学预防，并为遗传学和寄生虫学评估提供新的菌株。他们还将受益于我们在坎帕拉和托罗罗建立的研究疟疾寄生虫的实验室。我们认为，为了更好地描述抗药性，研究尚未失去培养中关键决定因素的新鲜菌株是至关重要的。我们的具体目标是：(1)评估疟疾寄生虫耐药性的选择性压力对用于疟疾治疗和化学预防的ACT的影响，(2)表征与药物敏感性降低相关的表型，以及(3)确定高水平耐药性的介体。我们的总体目标是在这一问题在非洲蔓延之前更好地确定抗疟疾耐药性和耐药性决定因素的特征，以便对这些决定因素的监测能够指导避免耐药性传播的努力。

 DESCRIPTION (provided by applicant): 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 resistance is increasing in Uganda, that the rise of resistance will be dampened and obscured by parasite fitness costs, but that continued drug pressure will allow emergence of resistant parasites that maintain adequate fitness to spread readily. Preemptive analysis of parasites will be critical to characterizing resistance mechanisms before the problem is widespread. To test our hypotheses we will monitor the drug sensitivities of malaria parasites isolated from Ugandan patients under varied levels of drug pressure; characterize the genetic profiles of these parasites; assess the fitness, virulence, and transmissibility costs of resistanc in both clinical and laboratory settings; and characterize high level resistance selected clinicall or in the laboratory. We believe that focused evaluations of fresh Ugandan isolates will best equip us to characterize 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 trials in Uganda, studying the treatment and chemoprevention of malaria, and providing fresh isolates for genetic and parasitological evaluation. They will also benefit from our established laboratories for the study of malaria parasites in Kampala and Tororo. We believe that, to well characterize resistance, it is essential to study fresh isolates that have not yet lost key determinants in culture. Our specifc aims will be: (1) to assess impacts of selective pressures for resistance of malaria parasites to ACTs used for the treatment and chemoprevention of malaria, (2) to characterize phenotypes associated with diminished drug sensitivity, and (3) to identify mediators of high level drug resistance. Our overall goal is to better characterize antimalarial drug resistance and resistance determinants before the problem becomes widespread in Africa, so that monitoring of these determinants can guide efforts to circumvent the spread of resistance.