Molecular epidemiology of drug resistance and population genetic structure of Pla

Pla耐药分子流行病学及群体遗传结构

• 批准号: 8103139
• 负责人: Fangli Lu
• 金额: $ 5.03万
• 依托单位: SUN YAT-SEN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8103139
• 关键词: Africa; Antimalarials; Attention; Biochemistry; Cessation of life; Characteristics; China; Chloroquine; Chloroquine resistance; Country; Data; Development; Dihydrofolate Reductase; Dihydropteroate Synthase; Drug resistance; Economic Development; Epidemiology; Evolution; Folic Acid Antagonists; Genes; Genetic Markers; Genetic Polymorphism; Genetic Population Study; Genetic Variation; Genotype; Geographic Distribution; Goals; Haplotypes; Health; Health Benefit; Human; In Vitro; Individual; Infection; Intervention; Island; Lead; Life; Longevity; Malaria; Measures; Methods; Microsatellite Repeats; Molecular; Molecular Epidemiology; Monitor; Morbidity - disease rate; Morphology; Mutation; Parasites; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Plasmodium falciparum; Point Mutation; Policies; Population; Prevalence; Province; Public Health; Pyrimethamine; Pyrimethamine-Sulfadoxine; Relapse; Reporting; Research; Resistance; Risk; Single Nucleotide Polymorphism; Southeastern Asia; Structure; Sulfadoxine; Sulfadoxine-pyrimethamine resistance; Suspension substance; Suspensions; Variant; Vivax Malaria; base; combat; disorder control; geographic population; in vivo; population genetic structure; programs; public health priorities; resistance mutation; resistant strain; transmission process

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.

描述（由申请人提供）：疟疾仍然是中国严重的公共卫生问题。在中国亚热带云南省和热带海南岛，疟疾是最流行的地方，恶性疟原虫和间日疟原虫传播率很高。然而，研究和干预方面的大部分注意力都集中在非洲和东南亚，中国对疟疾的研究很少。由于广泛使用，氯喹（CQ）现已因世界大部分地区出现耐药菌株而失去疗效。同时，暂停使用CQ导致CQ敏感性再次出现。但云南和海南的寄生虫在CQ抗性进化上存在差异，具体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，而赋予耐药性的点突变已在世界范围内广泛报道。记录 SP 耐药性的身份和程度对于抗疟药物的政策决策也至关重要。此外，间日疟原虫在包括中国在内的世界范围内造成了巨大的发病率，但传统上并未得到充分研究。基于此，我们本提案的长期目标是1）鉴定单核苷酸多态性（SNP）并表征云南和云南恶性疟原虫耐药位点的遗传多样性、种群结构和单倍型变异的地理分布。中国海南，2) 利用微卫星和 SNP 检查间日疟原虫的地理种群结构和遗传多样性水平，3) 为中国制定更有效的疟疾控制政策提供有价值的信息。近年来，我们发展了疟原虫遗传学、种群多样性和进化的分子方法，并利用遗传标记对云南和海南的疟原虫野外分离株进行了一些初步研究，从而使我们能够研究疟原虫的分子生物学特征。本提案中这些重要疟疾寄生虫的流行病学。具体目标是： 1. 确定中国云南省和海南省恶性疟原虫现场分离株中与 CQ 抗性 (CQR) 相关的遗传多态性。 2. 确定来自中国云南省和海南省的恶性疟原虫现场分离株中与 SP 抗性相关的 dhfr（乙胺嘧啶抗药性）和 dhps（磺胺多辛抗药性）基因中的点突变患病率。 3. 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，确定中国云南和海南间日疟原虫传播的地理结构和具体流行病学特征。 1 公共卫生相关性：该项目将对旨在识别和抗击耐药性疟疾的公共卫生计划产生重大益处，并有可能造福世界大部分人口的健康。这些数据将为延长个别抗疟药物的寿命以及在中国制定更合适的疟疾控制政策提供有价值的信息。