Integrated genomics research in parasitic tropical diseases

寄生虫病给全球公共卫生造成了巨大的损失。疟疾造成高达124万人死亡 人类丝虫病仍然是发展中世界残疾的一个主要原因。我们 建议把重点放在世界上两种最重要的寄生虫病病原体上， 顶端复合体血液寄生虫恶性疟原虫和丝虫线虫马来丝虫，引起 淋巴丝虫病。我们假设自然寄生虫种群中的基因组变异和可测量的 宿主、寄生虫和微生物组之间的相互作用可以被用来开发新的策略 控制、治疗和预防疟疾和丝虫病。最近的出现和可能的传播 东南亚抗青蒿素恶性疟疾有可能破坏消除疟疾的努力，以及 恶性疟原虫自然种群的广泛遗传变异是恶性疟原虫发育的主要障碍。 高度有效的疟疾疫苗。为监测和遏制抗药性提供新的工具 疟疾，我们将研究恶性疟原虫对青蒿素敏感性降低的遗传基础。 抗疟疾药物。我们还将确定寄主和寄生虫基因组中与自然保护性相关的基因座 对恶性疟原虫的获得性免疫，以努力建立保护的免疫关联，以告知 疫苗研发。寄生虫种群遗传变异的特征 生物疫苗将进行测试，这是朝着开发广泛有效的疫苗迈出的必要一步 疟疾疫苗。新的第三代长阅读测序平台将首次应用于 使用在单独资助的实地研究中收集的分离株对疟疾基因组进行测序和组装。为 丝虫病，多西环素是一种很有前途的新疗法，可以针对成虫，但更多的治疗 我们需要其他选择。我们将利用基因组和转录组数据确定新的丝虫病药物靶点 使用RNAi检查它们的功能和重要性。因为营养不良通常是地方病 丝虫病，我们还将检查受感染动物的代谢、转录和微生物组反应。 保持微量营养素缺乏的饮食。基因组学、流行病学和基础研究将整合在一起 在所有这些努力中，我们对疾病结局的决定因素和 促进开发控制和消除疟疾和丝虫病的新工具。

Parasitic diseases impose a tremendous toll on the global public health. Malaria causes up to 1.24 million deaths every year, while human filariasis remains a major cause of disability in the developing world. We propose to focus on two of the most important causative agents of parasitic disease in the world, the apicomplexan blood parasite Plasmodium falciparum, and the filarial nematode Brugia malayi, which causes lymphatic filariasis. We hypothesize that genomic variation in natural parasite populations and measurable interactions between host, parasites, and the microbiome can be exploited to develop novel strategies for control, treatment, and prevention of malaria and filariasis. The recent emergence and possible spread of artemisinin-resistant falciparum malaria in Southeast Asia threatens to derail malaria elimination efforts, and extensive genetic variation in natural populations of P. falciparum poses a major obstacle to the development of highly efficacious malaria vaccines. To provide new tools for surveillance and containment of drugresistant malaria, we will investigate the genetic basis of reduced susceptibility of P. falciparum to artemisinin antimalarial drugs. We will also identify loci in host and parasite genomes associated with protective naturally acquired immunity to P. falciparum in an effort to establish immune correlates of protection that can inform vaccine development. The characterization of genetic variation in parasite populations at sites where a whole organism vaccine will be tested represents a needed step toward the development of a broadly efficacious malaria vaccine. A new third generation long read sequencing platform will be applied for the first time to sequence and assemble malaria genomes using isolates collected in separately funded field studies. For filariasis, doxycycline is a promising new treatment that can target the adult worms, but more treatment alternatives are needed. We will identify novel filarial drug targets using genome and transcriptome data and examine their functionality and essentiality with RNAi. Because malnutrition is often co-endemic with filariasis, we will also examine the metabolic, transcriptomic, and microbiome response of infected animals kept on micronutrient deficient diets. Genomics, epidemiology, and fundamental research will be integrated in all of these endeavors to improve our understanding of the determinants of disease outcomes and facilitate the development of new tools for the control and elimination of malaria and filariasis.