Dissecting Chloroquine Resistance in the Plasmodium vivax Cross

剖析间日疟原虫交叉中的氯喹耐药性

• 批准号: 8682061
• 负责人: Jonathan J Juliano
• 金额: $ 24.7万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-11 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8682061
• 关键词: 6H,8H-3,4-dihydropyrimido(4,5-c)(1,2)oxazin-7-one; Africa; Aftercare; Alleles; Amino Acid Substitution; Antimalarials; Artemisinins; Biology; Blood; Cambodia; Chloroquine; Chloroquine resistance; Chromosome Mapping; Clinical; Cloning; Codon Nucleotides; Collaborations; Combined Modality Therapy; Country; Cross Infection; DNA; Development; Drug resistance; Event; Falciparum Malaria; Genetic; Genetic Crosses; Genomics; Goals; Growth; Hybrids; In Vitro; Indonesia; Infection; Laboratories; Life Cycle Stages; Malaria; Measurement; Methods; Modeling; Molecular; Monkeys; Morbidity - disease rate; Mutation; Orthologous Gene; Pan Genus; Parasite resistance; Parasitemia; Parasites; Parents; Persons; Pharmaceutical Preparations; Plasmodium falciparum; Plasmodium vivax; Public Health; Recombinants; Recrudescences; Research; Resistance; Resources; Risk; Rodent Model; Sampling; Southeastern Asia; Staging; Time; Transfection; United States National Institutes of Health; Variant; Vivax Malaria; artemisinine; base; comparative; genome sequencing; genome-wide; in vivo; indexing; innovation; interest; molecular marker; mortality; neglect; nonhuman primate; pressure; public health relevance; research study; resistance allele; resistance mechanism; resistant strain; response; tool

DESCRIPTION (provided by applicant): Despite the recent surge of interest in malaria, Plasmodium vivax has remained relatively neglected compared to falciparum malaria. Over 2.5 billion persons are at risk of vivax infection, which causes between 80 and 300 million cases per year. The principal drug in use today for vivax malaria is chloroquine (CQ) but its efficacy in now threatened by evolving resistance. Over the past 20 years, CQ resistance emerged in Western Pacifica and Southeast (SE) Asia and is now spreading worldwide. In some countries, such as Cambodia and Indonesia, the diminished efficacy of CQ therapy has prompted a change to artemisinin combination therapies (ACTs), which are significantly more costly, as first-line therapy for vivax malaria. The molecular basis of P. vivax CQ resistance remains unknown. Evidence indicates that the genetic events underlying P. vivax CQ resistance differs from P. falciparum as no association was found between in vivo drug responses and codon changes in Plasmodium vivax chloroquine resistance transporter (pvcrt), the P. vivax ortholog of Plasmodium falciparum chloroquine resistance transporter (pfcrt). Further research on CQ-resistant P. vivax has been severely hampered by the lack of critical tools to study the parasites including in vitro culture, DNA transfection and cloning methods. Therefore research on P. vivax CQ resistance depends on non-human primate models. Recently, the National Institutes of Health (NIH) invested significant resources to generate the first P. vivax genetic cross between a CQ sensitive strain and a CQ resistant strain in a chimpanzee. Using this cross, our proposal is aimed at determining the genetic loci underlying CQ resistance in P. vivax by conducting a linkage group selection (LGS) analysis leveraging whole genome sequencing of parental strains and in vivo mixed progeny infections before and after drug pressure. Without the need for traditional clonal analysis and defined IC50s, LGS identifies shifts toward resistant parental alleles after selection with CQ indicative of genetic loci associated with CQ resistance and has been used to successfully identify resistance alleles/mutations multiple times in malaria rodent models. This proposal is clearly significant for multiple reasons: 1) CQ resistant vivax is a major global public health problem causing significant morbidity and mortality with significant financial implications, 2) this will be the first genome-wide assessment for genetic loci of CQ resistance in vivax malaria using a defined genetic cross, 3) it leverages a set of samples from a unique and irreplaceable genetic cross generated in a chimpanzee, the approach which identified the key P. falciparum mutations for resistance to CQ and other antimalarials, 4) identification of CQ resistance mechanisms will aid in the development of additional antimalarials, and 5) identification of loci associated with CQ resistance will provide molecular markers of resistance, an important public health tool for studying the spread of resistance. The proposal is also innovative as it leverages new tools for conducting whole genome sequencing using hybrid capture to enrich parasite DNA and remove contaminating host DNA. Understanding the molecular basis for CQ resistance in P. vivax would be a major advance in understanding of vivax biology and has the potential to have profound impacts on global public health.

描述（由申请人提供）：尽管最近人们对疟疾的兴趣激增，但与恶性疟疾相比，间日疟原虫仍然相对被忽视。超过25亿人面临间日疟原虫感染的风险，每年导致8000万至3亿病例。目前用于间日疟疾的主要药物是氯喹（CQ），但其疗效目前尚不明显