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Plasmodium evolution and drug resistance in vitro and in populations using whole genome technologies.

机译:使用全基因组技术在体外和人群中的疟原虫进化和耐药性。

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摘要

Malaria remains a significant worldwide cause of morbidity and mortality. As drug resistance is widespread, there is a need to identify the mechanisms of action and resistance of current and novel compounds to leverage this knowledge for monitoring the emergence of resistance and to accelerate development of new drugs. Using a genomics approach, we show how whole-genome microarrays and deep sequencing can be used to advance our understanding of parasite biology. First, a custom high-density tiling array for Plasmodium falciparum was developed and validated, detecting nearly all mutations in the parasite genome. This technology was used to show that in vitro-derived P. falciparum parasites resistant to fosmidomycin have acquired of extra copies of 1-deoxy-D-xylulose 5-phosphate reductoisomerase, the presumed target. Second, we describe how whole-genome microarray analysis of 14 P. falciparum patient isolates from the Peruvian Amazon led to the discovery of clindamycin resistance, which is used for malaria treatment in Peru. We discovered a highly related parasite population in this region and identified the progeny of a natural cross. Additionally, we identified the genomic deletion of an important antigen for rapid diagnostic tests for malaria. Third, we describe using a custom microarray-based approach as well as deep sequencing for the study of a patient-derived P. vivax isolate. We show that microarray-based methods can detect thousands of SNPs in a patient isolate of P. vivax and the utility of whole-genome methods for genetic diversity studies. Last, we discuss ongoing work to characterize the mechanisms of action or resistance to several antimalarial compounds: piperaquine, decoquinate, mupirocin, and thiaisoleucine. The work described here provides a framework for future studies of in vitro drug resistance in and populations of malaria parasites.
机译:疟疾仍然是全世界发病率和死亡率的重要原因。随着耐药性的广泛传播,需要确定当前和新型化合物的作用机制和耐药性,以利用这一知识来监测耐药性的出现并加速新药的开发。使用基因组学方法,我们展示了如何使用全基因组微阵列和深度测序来增进我们对寄生虫生物学的理解。首先,开发并验证了定制的恶性疟原虫高密度切片阵列,可检测到寄生虫基因组中的几乎所有突变。这项技术被用来证明对磷霉素具有抗性的体外恶性疟原虫已经获得了额外的1-脱氧-D-木酮糖5-磷酸还原异构酶(假定的靶标)。第二,我们描述了从秘鲁亚马逊河对14株恶性疟原虫患者分离株进行全基因组微阵列分析如何导致对克林霉素耐药性的发现,该药物在秘鲁用于疟疾治疗。我们在该地区发现了一个高度相关的寄生虫种群,并确定了自然杂交的后代。此外,我们确定了重要抗原的基因组缺失,可快速诊断疟疾。第三,我们描述了使用自定义的基于微阵列的方法以及深度测序来研究患者衍生的间日疟原虫分离株。我们显示基于微阵列的方法可以检测到间日疟原虫患者分离株中的数千个SNP,以及全基因组方法在遗传多样性研究中的实用性。最后,我们讨论了正在进行的工作,以表征对几种抗疟疾化合物的作用或抗性机制:哌喹,去甲奎宁,莫匹罗星和噻异亮氨酸。此处描述的工作为今后在疟原虫和疟原虫种群中的体外耐药性研究提供了框架。

著录项

  • 作者

    Dharia, Neekesh Vijay.;

  • 作者单位

    The Scripps Research Institute.;

  • 授予单位 The Scripps Research Institute.;
  • 学科 Biology Bioinformatics.;Biology Parasitology.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 174 p.
  • 总页数 174
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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