Malaria parasite and vector genomics: transmission, pathology, and therapeutics

疟疾寄生虫和载体基因组学：传播、病理学和治疗学

• 批准号: 8710831
• 负责人: Daniel E Neafsey
• 金额: $ 53.45万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-10 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8710831
• 关键词: Affect; Basic Science; Biology; Cells; Cessation of life; Clinical; Collaborations; Collection; Commit; Communicable Diseases; Communities; Coupling; Cues; Culicidae; DNA; Development; Disease; Drug resistance; Evolution; Gene Family; Gene Frequency; Generations; Genes; Genomics; Health; Hybrids; Immune; Immune response; Insecticides; Investments; Knowledge; Malaria; Measures; Mediating; New Territories; Parasites; Pathogenesis; Pathology; Pharmaceutical Preparations; Pharmacotherapy; Plasmodium; Plasmodium falciparum; Play; Research Personnel; Resistance; Resources; Role; Sampling; Shapes; Technology; Testing; Thailand; Therapeutic; Vaccines; Whole-Genome Shotgun Sequencing; Work; design; disease transmission; disorder control; drug candidate; frontier; genome sequencing; genome wide association study; global health; innovation; microbiome; pathogen; tool; transcriptomics; transmission process; vector; vector mosquito

Malaria exerts the largest burden on global health of any disease caused by a eukaryotic parasite, and is responsible for approximately 600,000 deaths a year. Recent gains have been made in controlling malaria, but the proclivity for malaria parasites and their Anopheline mosquito vectors to evolve resistance to drugs and insecticides means that tools are needed to preserve the efficacy of existing therapeutics and control measures, and that investment in basic research is necessary to keep development pipelines stocked with new candidate drugs, vaccines, and insecticides. We propose to advance these efforts by coupling innovative applications of genomic technologies with key questions in the fields of malaria transmission, pathogenesis, and therapeutics. Our projects were specifically designed to leverage resources and expertise not commonly found outside of genome sequencing centers, and involve collaborations with leading investigators in the field. We will employ 16S sequencing, whole genome shotgun sequencing, and GWAS to test a hypothesis that mosquito innate immune genes play a role in shaping mosquito microbiome communities, which have been demonstrated to affect vectorial capacity (Aim 1). We will employ extremely sensitive single-cell transcriptomic profiling to bridge a key knowledge gap in the cues that cause P. falciparum parasites to commit to sexual differentiation, which is essential for transmission (Aim 2). We will create de novo assemblies of unprecedented quality to explore the heretofore uncharacterized genomic dark matter' of Plasmodium subtelomeres, where important antigenic gene families mediating pathogenesis reside and evolve (Aim 3). Finally, we will employ hybrid selection to enrich and sequence Plasmodium DNA from a critical 10 year longitudinal collection of clinical malaria samples from northwestern Thailand, a region where resistance to the current first line drug therapy (artemesinin) has recently arisen (Aim 4). We hypothesize that changes in allele frequency associated with resistance will be detectable in a longitudinal selection screen. The work we propose will not only push the frontier of malaria genomics into bold new territories, but generate empirical and analytical approaches applicable to a broad range of diseases.

在所有由真核寄生虫引起的疾病中，疟疾对全球健康造成的负担最大，并且 每年造成约 60 万人死亡。最近在控制疟疾方面取得了进展， 但疟疾寄生虫及其按蚊媒介进化出对药物的抗药性的倾向 和杀虫剂意味着需要工具来保持现有治疗和控制的功效 措施，并且有必要对基础研究进行投资，以保持开发渠道的充足 新的候选药物、疫苗和杀虫剂。我们建议通过耦合来推进这些努力 基因组技术的创新应用与疟疾传播领域的关键问题， 发病机制、治疗方法。我们的项目是专门为利用资源和专业知识而设计的 在基因组测序中心之外并不常见，并且涉及与领先的合作 实地调查人员。我们将采用16S测序、全基因组鸟枪法测序和GWAS来 检验蚊子先天免疫基因在塑造蚊子微生物群中发挥作用的假设 社区，已被证明会影响媒介能力（目标 1）。我们将聘用极其 敏感的单细胞转录组分析，以弥补导致 P. 恶性疟原虫进行性别分化，这对于传播至关重要（目标 2）。我们将 创建前所未有的质量的从头组装，以探索迄今为止未表征的基因组 疟原虫亚端粒的暗物质，其中重要的抗原基因家族介导发病机制 生存和发展（目标 3）。最后，我们将采用杂交选择来富集疟原虫 DNA 并对其进行测序 来自泰国西北部地区临床疟疾样本的关键 10 年纵向收集 最近出现了对当前一线药物治疗（青蒿素）的耐药性（目标 4）。我们 假设与耐药性相关的等位基因频率的变化可以在纵向中检测到 选择屏幕。我们提出的工作不仅将疟疾基因组学的前沿推向大胆的新领域 领域，但产生了适用于广泛疾病的经验和分析方法。