Resistance of Malaria Parasites to Artemisinin-Based Therapies

 描述（申请方提供）：非洲疟疾的控制和最终消除受到抗药性的严重挑战，特别是对新的青蒿素类复方疗法的抗药性。令人担忧的迹象表明，对青蒿素综合疗法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，因为大部分严重的恶性疟疾发生在非洲大陆。改进耐药程度和耐药机制的表征至关重要。我们假设，抗疟药物耐药性正在增加，在乌干达，耐药性的上升将被抑制和掩盖寄生虫健身成本，但持续的药物压力将允许出现耐药寄生虫，保持足够的健身容易传播。在问题广泛传播之前，对寄生虫进行先发制人的分析对于表征耐药机制至关重要。为了检验我们的假设，我们将监测药物敏感性的疟疾寄生虫分离乌干达患者在不同水平的药物压力;表征这些寄生虫的遗传特征;评估健身，毒力和传播成本的阻力，在临床和实验室设置;和表征高水平的电阻选择clinicall或在实验室。我们相信，集中评估新鲜的乌干达分离株将最好地装备我们的特点出现在非洲，疟疾问题是最大的高水平的电阻，并及时表征的电阻机制可以是最有价值的。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，并提供用于遗传和寄生虫学评估的新鲜分离物。他们还将受益于我们在坎帕拉和托罗罗建立的疟疾寄生虫研究实验室。我们认为，为了更好地表征耐药性，研究尚未在培养中失去关键决定因素的新鲜分离株至关重要。我们的具体目标是：（1）评估疟疾寄生虫对用于治疗和化学预防疟疾的青蒿素综合疗法产生抗药性的选择压力的影响，（2）描述与药物敏感性降低相关的表型，（3）确定高水平抗药性的介质。我们的总体目标是在非洲出现广泛的抗疟药物耐药性和耐药性决定因素之前，更好地确定这些因素的特征，以便对这些决定因素的监测能够指导防止耐药性蔓延的努力。

 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.