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）正在协调一项积极的努力，以遏制东南亚的青蒿素耐药恶性疟原虫疟疾，防止其从柬埔寨西部最近出现的地点蔓延。由于缺乏监测工具，无法追踪抵抗从其发源地蔓延的程度和方向，遏制工作受到阻碍。目前还没有青蒿素抗药性的分子抗药性标记，例如用来检测对氯喹和其他抗疟药物抗药性的标记。如果没有这些标记，绘制青蒿素耐药性图谱的唯一手段就是进行青蒿琥酯单一疗法的临床试验，这就限制了指导遏制努力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的耐药性很有价值，缅甸是该地区疟疾最多的国家。我们建议与缅甸的科学家合作，对恶性疟原虫种群结构和基因流动进行试点研究，为随后的研究做准备，以验证候选的青蒿素抗性标记。我们将在缅甸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供资的抗疟药物疗效研究的存档样本，以及观察性横断面调查。从这些样本中提取的DNA将进行寄生虫种群遗传学分析，以衡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抗药性的努力。我们还将分析样本中是否存在青蒿素联合疗法（ACT）伙伴药物耐药性的分子标志物，并在获得这些标志物后，分析新出现的青蒿素耐药性候选标志物。这项试点研究将产生关于已知耐药标志物的程度和流行率的有用数据，并为帮助验证新的候选标志物作为临床耐药预测因子奠定基础。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，旨在验证青蒿素抗性标记，并得到未来R01和其他赠款的支持。据我们所知，这将是美国国立卫生研究院第一笔直接在缅甸境内开展工作的赠款，缅甸对亚洲的疟疾控制和耐药性遏制工作至关重要。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，用于跟踪和遏制东南亚和其他地区的青蒿素耐药性。

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.