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

在由真核寄生虫引起的任何疾病中，疟疾对全球健康造成的负担最大，而且 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对药物产生抗药性的倾向 而杀虫剂意味着需要工具来保持现有疗法和防治的有效性。 措施，对基础研究的投资是必要的，以保持开发管道的储备 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 基因组技术在疟疾传播领域的关键问题的创新应用， 发病机制和治疗方法。我们的项目专门为利用资源和专业知识而设计 在基因组测序中心之外并不常见，而且涉及到与领先的 该领域的调查人员。我们将采用16S测序、全基因组鸟枪式测序和GWAS来 检验一种假设，即蚊子的先天免疫基因在形成蚊子微生物群中发挥了作用 社区，已被证明影响媒介能力(目标1)。我们将极大地雇佣 灵敏的单细胞转录图谱，弥合导致P的线索中的关键知识缺口。 恶性疟原虫承诺进行性分化，这对传播至关重要(目标2)。我们会 创造前所未有的质量的新组装，以探索迄今尚未确定的基因组 疟原虫端粒下的暗物质，其中重要的抗原基因家族介导了发病 居住和进化(目标3)。最后，我们将使用杂交选择来丰富和测序疟原虫DNA 来自泰国西北部一个地区为期10年的疟疾临床样本的关键纵向收集 最近出现了对当前一线药物疗法(青蒿素)的抗药性(目标4)。我们 假设与抗性相关的等位基因频率的变化将在纵向上被检测到 选择屏幕。我们提出的工作不仅将把疟疾基因组学的前沿推向大胆的新的 但产生了适用于各种疾病的经验和分析方法。

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.