Pilot studies of the molecular epidemiology of drug-resistant malaria in Myanmar

描述（由申请人提供）：世界卫生组织（世卫组织）正在协调一项积极努力，在东南亚遏制具有青蒿素耐药性的恶性疟原虫疟疾，防止其从最近在柬埔寨西部出现的地点传播开来。由于缺乏监测工具来跟踪耐药性从源头扩散的程度和方向，这种遏制努力受到阻碍。用于检测对氯喹和其他抗疟疾药物耐药性的分子耐药性标记尚未可用于检测青蒿素耐药性。如果没有这种标记，绘制青蒿素耐药性的唯一手段就是进行青蒿琥酯单一疗法的临床试验，从而限制了指导遏制工作所需的耐药性数据的全面性和及时性。因此，青蒿素耐药性的分子标记对于监测缅甸（以前称为缅甸）的耐药性是有价值的，缅甸是该地区疟疾最严重的国家。我们建议与缅甸科学家合作，开展恶性疟原虫种群结构和基因流动的试点研究，为后续验证候选青蒿素耐药标记的研究做准备。我们将在缅甸各地的几个地点收集和分析恶性疟原虫感染者的滤纸血样。样本来源将包括已完成和单独资助的抗疟药物疗效研究的存档样本，以及一项观察性横断面调查。将对从这些样本中提取的DNA进行寄生虫种群遗传学分析，以测量种群结构和基因流动的程度，这些信息将有助于指导遏制耐药性的工作。我们还将分析样品中是否存在对以青蒿素为基础的联合治疗（ACT）伴生药物耐药的分子标记，并在这些标记可用时分析新出现的候选青蒿素耐药标记。这项初步研究将产生关于已知耐药标记物的范围和流行程度的有用数据，并为帮助验证作为临床耐药预测因子的新候选标记物奠定基础。此外，该项目将为美国和缅甸之间的后续研究合作奠定基础，目的是在未来R01和其他赠款的支持下验证青蒿素耐药性标记。据我们所知，这将是美国国立卫生研究院首次直接在缅甸境内开展工作，缅甸是一个对亚洲疟疾控制和遏制耐药性工作具有重要意义的国家。该项目将与下缅甸医学研究部世卫组织疟疾研究和培训合作中心的分子和临床研究人员合作开展。预计这项工作将有助于开发强有力的监测工具，用于跟踪和控制东南亚和其他地方的青蒿素耐药性。

DESCRIPTION (provided by applicant): The World Health Organization (WHO) is coordinating an aggressive effort to contain artemisinin resistant Plasmodium falciparum malaria in Southeast Asia before it spreads from its recent site of emergence in Western Cambodia. This containment effort is hampered by the lack of surveillance tools to track the extent and direction of the spread of resistance from its focus of origin. Molecular resistance markers such as those used to detect resistance to chloroquine and other antimalarial drugs are not yet available for artemisinin resistance. Without such markers, the only means of mapping artemisinin resistance is to perform clinical trials of artesunate monotherapy, limiting the comprehensiveness and timeliness of resistance data needed to guide containment efforts. A molecular marker of artemisinin resistance would therefore be valuable for surveillance of resistance in Myanmar (formerly known as Burma), the country with the most malaria of any in the region. We propose to work with scientists in Myanmar to conduct a pilot study of P. falciparum population structure and gene flow in preparation for subsequent studies to validate candidate artemisinin resistance markers. We will collect and analyze filter paper blood samples from P. falciparum-infected individuals at several sites across Myanmar. Sources of samples will include archived samples from completed and separately funded antimalarial drug efficacy studies, and an observational cross-sectional survey. DNA extracted from these samples will be subjected to parasite population genetics analyses to measure the extent of population structure and gene flow, information that will be useful in guiding resistance containment efforts. We will also analyze samples for the presence of molecular markers of resistance to artemisinin-based combination therapy (ACT) partner drugs and, as they become available, emerging candidate markers of artemisinin resistance. This pilot study will generate useful data on the extent and prevalence of known resistance markers, and lay the groundwork to help to validate new candidate markers as predictors of clinical resistance. Moreover this project will build a foundation for subsequent research collaboration between the U.S. and Myanmar aimed at validating artemisinin resistance markers with support from future R01 and other grants. To our knowledge this will be the first NIH grant awarded to work directly inside Myanmar, a country of major importance to malaria control and drug resistance containment efforts in Asia. The project will be conducted in collaboration with molecular and clinical investigators at the WHO Collaborating Center for Research and Training on Malaria in the Department of Medical Research, Lower Myanmar. This work is expected to contribute to the development of robust surveillance tools that can be used to track and contain artemisinin resistance in Southeast Asia and elsewhere.