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

描述(申请人提供)：世界卫生组织(WHO)正在协调一项积极努力，在东南亚遏制抗青蒿素恶性疟原虫疟疾，防止其从柬埔寨西部最近出现的地点传播。由于缺乏监测工具来跟踪耐药性从其源头扩散的程度和方向，这一遏制努力受到了阻碍。青蒿素耐药性的分子耐药性标记物，如用于检测对氯喹和其他抗疟疾药物耐药性的标记物，尚不存在。如果没有这样的标记，绘制青蒿素耐药性图的唯一手段是进行青蒿琥酯单一疗法的临床试验，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，青蒿素抗药性的分子标记对于监测缅甸(前身为缅甸)的抗药性是有价值的，缅甸是该地区疟疾最严重的国家。我们建议与缅甸的科学家合作，对恶性疟原虫的种群结构和基因流动进行初步研究，为后续研究验证候选青蒿素抗性标记做准备。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疾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将接受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抗药性控制工作。我们还将分析样本中是否存在青蒿素联合疗法(ACT)合作药物的耐药分子标记，以及当它们可用时，新出现的青蒿素耐药候选标记。这项初步研究将产生有关已知耐药标记的范围和流行率的有用数据，并为验证新的候选标记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，这些合作旨在验证青蒿素耐药性标记，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授予的第一笔直接在缅甸境内工作的赠款，缅甸是一个对亚洲疟疾控制和耐药性控制工作至关重要的国家。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调查人员合作进行。这项工作预计将有助于开发强大的监测工具，可用于追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.