Molecular epidemiology of drug resistance and population genetic structure of Pla

描述（申请人提供）：疟疾在中国仍然是一个严重的公共卫生问题。在亚热带的云南省和热带的中国海南岛，疟疾是最流行的，恶性疟原虫和间日疟原虫都是高传播的。然而，在研究和干预方面，大多数注意力集中在非洲和东南亚，很少有关于中国疟疾的研究。由于氯喹的广泛使用，由于在世界大多数地区出现耐药菌株，氯喹现已失去效力。同时，暂停使用CQ导致了CQ敏感性的重新出现。然而，云南和海南寄生虫对CQ的抗性进化存在差异，其确切机制有待进一步研究。磺胺多辛-乙胺嘧啶（SP）靶向恶性疟原虫的dhfr和dhps基因，并在世界范围内广泛报道了产生耐药性的点突变。记录SP耐药性的特征和程度对抗疟药物的政策决定也至关重要。此外，间日疟原虫在包括中国在内的世界上造成了很大的发病率负担，但传统上一直没有得到充分的研究。基于此，我们的长期目标是：1)鉴定云南和海南恶性疟原虫耐药位点的单核苷酸多态性（SNP），并表征遗传多样性的地理分布、种群结构和单倍型变异；2)利用微卫星和SNP检测间日疟原虫的地理种群结构、遗传多样性水平；3)为中国制定更有效的疟疾控制政策提供有价值的信息。在过去的几年里，我们发展了分子方法来研究疟疾寄生虫的遗传学、种群多样性和进化，并利用遗传标记对云南和海南的疟疾分离株进行了初步的研究，从而使我们能够研究这些重要的疟疾寄生虫的分子流行病学。具体目标是：1。云南省和海南省恶性疟原虫CQ抗性基因多态性分析2 .测定云南省和海南省恶性疟原虫与SP耐药相关基因dhfr（乙胺嘧啶耐药）和dhps（磺胺多辛耐药）点突变流行率。利用pvcsp、pvmsp1、pvmsp3-1基因和微卫星标记评估间日疟原虫基因型的变化，并确定中国云南和海南间日疟原虫传播的地理结构和特定流行病学特征。1公共卫生相关性：该项目将对旨在识别和对抗耐药疟疾的公共卫生计划产生重大益处，并有可能造福世界上相当大比例人口的健康。这些数据将为中国延长单个抗疟药物的使用寿命和制定更合适的疟疾控制政策提供有价值的信息。

DESCRIPTION (provided by applicant): Malaria remains a serious public health problem in China. In the subtropical Yunnan Province and the tropical Hainan Island of China, malaria has been the most endemic with high transmission of both Plasmodium falciparum and P. vivax. However, most of the attention in terms of research and interventions has been focused in Africa and Southeast Asia, very few studies of malaria in China have been conducted. Because of extensive use, chloroquine (CQ) has now lost its efficacy due to the emergence of resistant strains in most parts of the world. Meanwhile, suspension of the use of CQ has resulted in reappearance of CQ sensitivity. However, there were differences in the evolution of CQ resistance between parasites from Yunnan and Hainan, the exact mechanism needs to be investigated. Sulfadoxine-pyrimethamine (SP) targets the dhfr and dhps genes of P. falciparum, and point mutations that confer resistance have been widely reported worldwide. Documenting the identity and extent of SP resistance is also critical for policy decisions regarding antimalarial drugs. In addition, P. vivax causes a large burden of morbidity in the world including China but traditionally has been understudied. Based on these, our long-term goal of this proposal is 1) to identify single-nucleotide polymorphism (SNP) and characterize the geographic distribution of genetic diversity, population structure, and haplotype variability at drug resistant loci of P. falciparum from Yunnan and Hainan, China, 2) to examine the geographic population structure, levels of genetic diversity of P. vivax using microsatellite and SNP, and 3) to yield valuable information for making more effective malaria control policies in China. In the past several years we have developed the molecular methods to study the genetics, population diversity, and evolution of malaria parasites, and have done some preliminary studies on malaria field isolates from Yunnan and Hainan using genetic markers, thus enabling us to study the molecular epidemiology of these important malaria parasites in this proposal. The specific aims are to: 1. Determine genetic polymorphisms associated with CQ resistance (CQR) in P. falciparum field isolates from Yunnan and Hainan provinces, China. 2. Determine the point mutation prevalence in the dhfr (pyrimethamine drug resistance) and dhps (sulfadoxine drug resistance) genes associated with SP resistance in P. falciparum field isolates from Yunnan and Hainan provinces, China. 3. Assess the changes of P. vivax genotypes using pvcsp, pvmsp1, pvmsp3-1 genes, and microsatellite markers and determine the geographic structure and specific epidemiological characteristics of P. vivax transmission in Yunnan and Hainan, China. 1 PUBLIC HEALTH RELEVANCE: The project will be of significant benefit to public health programs aimed at identifying and combating drug-resistant malaria, and have the potential to benefit the health of a substantial proportion of the world's population. The data will provide valuable information for extending the life span of individual antimalarial drugs and developing more appropriate malaria control policies in China.