Integrated genomics research in parasitic tropical diseases

寄生虫病给全球公共卫生造成巨大损失。疟疾导致多达124万人 在发展中国家，人类丝虫病仍然是造成残疾的主要原因。我们 建议重点关注世界上两种最重要的寄生虫病病原体， 顶端复形血液寄生虫恶性疟原虫和马来丝虫， 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用来开发新的策略， 控制、治疗和预防疟疾和丝虫病。最近出现和可能蔓延的 东南亚的青蒿素耐药性恶性疟疾有可能破坏消除疟疾的努力， 恶性疟原虫自然种群中广泛的遗传变异对恶性疟原虫的发展构成了主要障碍 高效的疟疾疫苗。为监测和遏制抗药性提供新的工具 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。我们还将确定宿主和寄生虫基因组中与保护性天然 获得性免疫力的恶性疟原虫，努力建立免疫相关的保护，可以告知 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读段测序平台将首次应用于 利用在单独资助的实地研究中收集的分离株进行疟疾基因组测序和组装。为 多西环素是一种很有前途的新治疗方法，可以靶向蠕虫，但更多的治疗方法 需要有替代办法。我们将利用基因组和转录组数据确定新的丝虫药物靶点， 用RNAi来检验它们的功能和重要性。因为营养不良往往与 我们还将研究受感染动物的代谢、转录组和微生物组反应 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被整合 在所有这些努力，以提高我们对疾病结果的决定因素的理解， 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.