Determinants of growth and fitness in drug resistant malaria parasites

耐药疟疾寄生虫生长和健康的决定因素

• 批准号: 8206639
• 负责人: Michael T Ferdig
• 金额: $ 35.92万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8206639
• 关键词: Accounting; Address; Africa; Alleles; Antimalarials; Architecture; Automobile Driving; Bioinformatics; Biological; Biological Process; Biology; Candidate Disease Gene; Cell physiology; Chemicals; Chloroquine; Chloroquine resistance; Chromosome Mapping; Code; Complement; Complex; Control Locus; Copy Number Polymorphism; Crystallization; DNA; Data; Databases; Development; Dimensions; Disease; Drug resistance; Drug usage; Erythrocytes; Event; Evolution; Exhibits; Future; Gene Amplification; Gene Chips; Gene Dosage; Gene Expression; Genes; Genetic; Genetic Crosses; Genetic Polymorphism; Genetic Transcription; Genetic Variation; Genome; Genome Mappings; Genomics; Goals; Growth; Health; Human; In Vitro; Inherited; Institutes; Intervention; Knowledge; Laboratories; Lead; Left; Letters; Link; Location; Malaria; Maps; Measures; Methodology; Methods; Molecular; Multi-Drug Resistance; Mutation; Parasite resistance; Parasites; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Physiological; Physiology; Plasmodium falciparum; Point Mutation; Population; Positioning Attribute; Principal Investigator; Production; Published Comment; Quantitative Trait Loci; Regulation; Regulatory Element; Relative (related person); Research; Resistance; Resolution; Role; Solutions; Structure; Therapeutic; Time; Transcript; Transcriptional Regulation; Trees; Vacuole; Variant; Virulence; comparative; cost; fitness; gene function; genetic linkage; genome sequencing; genome-wide; hemozoin; insertion/deletion mutation; insight; killings; mutant; neglect; novel strategies; parasite genome; pressure; programs; resistance mutation; segregation; tool; trait

DESCRIPTION (provided by applicant): The malaria parasite, Plasmodium falciparum, continues to devastate human health. The emergence and spread of multi-drug resistant (MDR) parasites following decades of over-use of chloroquine (CQ) is of fundamental significance to current malaria control efforts. The near-global selective sweep of the K76T- encoding mutation in the CQ resistance (CQR) gene, pfcrt, left behind an adapted genome impacting parasite growth, fitness, and a propensity for rapid MDR evolution. The long-term goal of this project is to identify the molecular components of this resistance-adapted genome. Our hypothesis is that there is an essential genetic background of CQR parasites, comprising networked gene actions that compensate for altered PfCRT function and stabilize parasite physiology and growth in the absence of drug pressure. To detect the genome-wide presence of these drug resistance adaptations, we focus on basic growth and normal cellular processes in two different parasite solutions to historical drug pressure: 1) progeny of a genetic cross that maintain a common pfcrt allele in a segregating CQR/MDR background; 2) a spectrum of laboratory-selected pfcrt mutant lines in a single controlled genetic background. Our Specific Aims build upon a detailed analysis of growth and physiological traits in the absence of drug to drive a genome-wide search for the gene networks controlling key parameters of fitness. Specific Aim 1. To precisely quantify growth and physiological parameters as indicators of parasite fitness in cultured red blood cells. We will use QTL mapping of these inter- related traits to pinpoint genome regions to facilitate searches for key genes using powerful emerging comparative databases and tools. Specific Aim 2. To identify strain-specific shifts in pfcrt-mutant transcription profiles and to map expression (e)QTL controlling inheritance of expression level traits. Specific Aim 3. To identify genome structural variants associated with CQ-selection. We will determine copy number polymorphisms in genes known to be associated with drug resistance and use high resolution CGH identification of gene copy number variations, small deletions, and some SNPs throughout the genome. Formal integration of these layers of independent but complimentary whole-genome biological data highlights a novel approach to elucidate new avenues for antimalarial intervention. Project Narrative: Malaria kills more than 2 million kids in Africa and infects more than 500 million people worldwide each year. The recently completed /Plasmodium falciparum /comparative genome sequencing project at the Broad Institute provides a vast view of genetic diversity of this species; however, few methods have been developed to use this information. Our proposal uses a combination of classical genetic linkage mapping with new tools to study gene expression variation and chromosomal structural variation around the entire genome. An integration of these tools will facilitate the mapping of the molecular determinants of fitness and virulence in dangerous multi-drug resistant malaria parasites. This knowledge will lead to new avenues of attack against this disease.

描述（由申请人提供）：疟原虫恶性疟原虫继续破坏人类健康。几十年来过度使用氯喹（CQ）后，多重耐药（MDR）寄生虫的出现和传播对于当前的疟疾控制工作具有根本意义。 CQ 抗性 (CQR) 基因 pfcrt 中 K76T 编码突变的近乎全局选择性清除，留下了影响寄生虫生长、适应性和快速 MDR 进化倾向的适应基因组。该项目的长期目标是确定这种抗性适应基因组的分子成分。我们的假设是，CQR 寄生虫有一个重要的遗传背景，包括网络化的基因作用，可以补偿 PfCRT 功能的改变，并在没有药物压力的情况下稳定寄生虫的生理和生长。为了检测这些耐药性适应在全基因组范围内的存在，我们重点关注两种不同寄生虫对历史药物压力的解决方案中的基本生长和正常细胞过程：1）在分离的 CQR/MDR 背景下维持共同 pfcrt 等位基因的遗传杂交的后代； 2) 在单一受控遗传背景下实验室选择的一系列 pfcrt 突变株系。我们的具体目标建立在对无药物情况下生长和生理特征的详细分析的基础上，以推动全基因组搜索控制健康关键参数的基因网络。具体目标 1. 精确量化生长和生理参数，作为培养红细胞中寄生虫适应性的指标。我们将使用这些相互关联性状的 QTL 作图来精确定位基因组区域，以便于使用强大的新兴比较数据库和工具来搜索关键基因。具体目标 2. 鉴定 pfcrt 突变体转录谱中的菌株特异性变化，并绘制控制表达水平性状遗传的表达 (e)QTL。具体目标 3. 鉴定与 CQ 选择相关的基因组结构变异。我们将确定已知与耐药性相关的基因的拷贝数多态性，并使用高分辨率 CGH 识别整个基因组中的基因拷贝数变异、小缺失和一些 SNP。这些独立但互补的全基因组生物数据层的正式整合凸显了一种阐明抗疟干预新途径的新方法。 项目叙述：疟疾每年在非洲夺去超过 200 万儿童的生命，并在全球范围内感染超过 5 亿人。布罗德研究所最近完成的/恶性疟原虫/比较基因组测序项目提供了该物种遗传多样性的广阔视野；然而，已经开发出很少的方法来使用这些信息。我们的建议结合了经典的遗传连锁图谱和新工具来研究整个基因组的基因表达变异和染色体结构变异。这些工具的整合将有助于绘制危险的多重耐药疟疾寄生虫的适应性和毒力的分子决定因素。这些知识将带来对抗这种疾病的新途径。

项目成果

Genome-wide compensatory changes accompany drug- selected mutations in the Plasmodium falciparum crt gene.

• DOI: 10.1371/journal.pone.0002484
• 发表时间: 2008-06-25
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Jiang H;Patel JJ;Yi M;Mu J;Ding J;Stephens R;Cooper RA;Ferdig MT;Su XZ
• 通讯作者: Su XZ

Functional analysis of sirtuin genes in multiple Plasmodium falciparum strains.

• DOI: 10.1371/journal.pone.0118865
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Merrick CJ;Jiang RH;Skillman KM;Samarakoon U;Moore RM;Dzikowski R;Ferdig MT;Duraisingh MT
• 通讯作者: Duraisingh MT

Viral organization of human proteins.

• DOI: 10.1371/journal.pone.0011796
• 发表时间: 2010-08-25
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Wuchty S;Siwo G;Ferdig MT
• 通讯作者: Ferdig MT

Quantitative trait loci mapping reveals candidate pathways regulating cell cycle duration in Plasmodium falciparum.

• DOI: 10.1186/1471-2164-11-577
• 发表时间: 2010-10-18
• 期刊: BMC genomics
• 影响因子: 4.4
• 作者: Reilly Ayala HB;Wacker MA;Siwo G;Ferdig MT
• 通讯作者: Ferdig MT