Host-specific cell surface receptors on African trypanosomes

描述（由申请方提供）：有鞭毛的原生动物寄生虫布氏锥虫是非洲锥虫病的病原体，导致撒哈拉以南非洲地区人类和牲畜的广泛死亡和发病。昏睡病如果不治疗是致命的，但没有疫苗存在，目前的治疗方法是旧的，有毒的，难以管理。因此，迫切需要进行研究，以更好地了解这些寄生虫，并促进新的治疗干预措施的开发。T.布鲁氏菌在哺乳动物和采采蝇宿主之间交替，必须整合来自外部环境的信号，以便在两种宿主中生存、发育和致病。寄生虫表面蛋白保护宿主免疫防御，允许获得营养物质，并提供对宿主-寄生虫相互作用和发病机制重要的感觉和信号功能。因此，细胞表面蛋白对T.布氏杆菌，并成为昏睡病治疗干预的有吸引力的目标。迄今为止，没有系统的研究寄生虫表面蛋白质组已进行和关键的表面暴露的蛋白质仍然是未知的。这代表了我们对锥虫生物学和宿主-寄生虫界面理解的一个主要空白。通过结合亲和纯化细胞表面蛋白质与国家的最先进的蛋白质组学和一个开拓性的方法分离完整的鞭毛，我们现在能够确定的表面蛋白质组的T。布氏杆菌，包括专门用于信号传导和宿主-寄生虫相互作用的表面亚结构域。我们的目标是利用我们的蛋白质组学方法来定义T。来自昆虫和哺乳动物血流的布鲁氏菌细胞表面形成寄生虫。从这些数据和我们的鞭毛蛋白质组，我们将确定主机特定的表面蛋白，这将是一个哺乳动物宿主感染的影响进行测试。而我们的重点是T. brucei，我们希望我们的研究结果是广泛的兴趣，为社会研究基础生物学和致病性的寄生原虫。 公共卫生相关性：非洲锥虫是毁灭性的人类和动物病原体，造成严重的人类死亡和限制经济发展。锥虫必须整合许多细胞外信号才能传播并引起疾病，但负责这些功能的细胞表面蛋白在很大程度上是未知的。目前的建议旨在确定和研究对哺乳动物感染重要的锥虫表面蛋白，这将提供更好地了解锥虫生物学的一个关键但知之甚少的方面，并可能揭示新的治疗靶点。

DESCRIPTION (provided by applicant): The flagellated protozoan parasite Trypanosoma brucei is responsible for African trypanosomiasis, which causes widespread mortality and morbidity of humans and livestock in sub-Saharan Africa. Sleeping sickness is fatal if untreated, yet no vaccine exists and current treatments are old, toxic and difficult to administer. Thus, there is a pressing need for research to better understand these parasites and facilitate development of new therapeutic interventions. T. brucei alternates between mammalian and tsetse fly hosts and must integrate signals from the external environment for survival, development and pathogenesis in both hosts. Parasite surface proteins protect against host immune defenses, allow acquisition of nutrients and provide sensory and signaling functions important for host-parasite interactions and pathogenesis. Cell surface proteins are thus critical for the parasitic life-style of T. brucei and make attractive targets for therapeutic intervention in sleeping sickness. To date, no systematic study of the parasite surface proteome has been conducted and key surface-exposed proteins remain mostly unknown. This represents a major gap in our understanding of trypanosome biology and the host-parasite interface. By combining affinity purification of cell surface proteins with state-of-the-art proteomics and a pioneering method for isolating intact flagella, we are now able to define the surface proteome of T. brucei, including surface sub-domains that are specialized for signaling and host-parasite interaction. Our goals are to capitalize on our proteomics approach to define the complete protein repertoire of the T. brucei cell surface from insect and mammalian bloodstream form parasites. From these data and our flagellum proteome, we will identify host-specific surface proteins, which will be tested for an impact on infection of the mammalian host. While our focus is on the host-parasite interface of T. brucei, we expect our results to be of wide interest for the community studying fundamental biology and pathogenesis of parasitic protozoa. PUBLIC HEALTH RELEVANCE: African trypanosomes are devastating human and animal pathogens that cause significant human mortality and limit economic development. Trypanosomes must integrate numerous extracellular signals to be transmitted and cause disease, but the cell surface proteins responsible for these functions are largely unknown. The current proposal aims to identify and study trypanosome surface proteins important for mammalian infection, which will provide better understanding of a critical, yet poorly understood aspect of trypanosome biology and may reveal new therapeutic targets.