Identification of factors contributing to group behavior in African Trypanosomes

描述(申请人提供)：布鲁氏锥虫是一种有鞭毛的原生动物寄生虫，是人类非洲昏睡病和牛的nagana的病原体。昏睡病是撒哈拉以南非洲的一种新出现的疾病，那里约有6000万人生活在感染的风险中。如果不治疗昏睡病，而且没有疫苗可用，昏睡病是致命的。目前的药物是过时的、有毒的和难以管理的，这种情况因耐药性的发展而加剧。因此，迫切需要了解寄生虫生物学的新特征，并确定新的药物靶点。布鲁氏毛滴虫通过被感染的采采蝇媒介叮咬而传播到哺乳动物宿主的血液中。在这两种宿主中，布氏毛滴虫都与组织表面密切接触，并表现出对传感和信号的隐含要求，以引导寄生虫的迁移和分化。这一点在采采纸中尤为明显。目前，人们对表面接触如何调节锥虫生物学知之甚少。最近，我们报道了布鲁氏毛滴虫在半固体琼脂糖板上培养时的社会行为。这种行为被称为社会运动，其特征是形成多细胞群落，这些群落感知外部刺激并相互沟通，以协调种群的运动。布鲁氏锥虫社会行为的发现揭示了原生动物行为的复杂性和协同性，这在以前是没有被认识到的。在其他微生物病原体中，社会行为提供了许多优势，对细菌中社会相互作用的研究彻底改变了我们对微生物发病机制的理解。我们假设，布鲁氏锥虫的社会行为为锥虫的发育和致病提供了类似的优势，并且布鲁氏锥虫在社会运动中用于细胞-细胞信号传递的系统与用于感知和响应宿主信号的系统重叠。目前的提案将确定锥虫社会行为的基因和机制。考虑到其他微生物之间广泛的社会互动，我们预计我们的研究将在寄生原生动物之间具有广泛的相关性。 公共卫生意义：非洲锥虫和相关寄生虫是全世界数百万人发病和死亡的根源，由这些病原体引起的疾病是世界上最被忽视的疾病之一。拟议的项目将确定锥虫社会行为所需的基因和机制。在细菌病原体中，社会相互作用对疾病的发病机制有深远的影响，但这一范式最近才应用于寄生虫，因此我们希望发现新的概念和机制，广泛适用于其他寄生虫感染。

DESCRIPTION (provided by applicant): Trypanosoma brucei is a flagellated protozoan parasite that is the causative agent of African sleeping sickness in humans and nagana in cattle. Sleeping sickness is a reemerging disease in sub-Saharan Africa where ~60 million people live at risk of infection. Sleeping sickness is fatal if untreated and no vaccines are available. Current drugs are antiquated, toxic and difficult to administer, a situation that is exacerbated by the development of drug resistance. Thus, there is a critical and urgent need to understand novel features of parasite biology and identify new drug targets. T. brucei is transmitted to the bloodstream of a mammalian host through the bite of an infected tsetse fly vector. In both hosts, T. brucei is in intimate contact with tissue surfaces and exhibits an implicit requirement for sensing and signaling to guide parasite migration and differentiation. This is especially apparent in the tsetse. Currently, little is known about how surface contact modulates trypanosome biology. Recently, we reported that T. brucei engages in social behavior when cultivated on semi-solid agarose plates. This behavior, termed social motility, is characterized by the formation of multicellular communities that sense external stimuli and communicate with one another to coordinate movement of the population. The discovery of social behavior in T. brucei reveals a level of complexity and cooperativity in protozoan behavior that was previously unrecognized. In other microbial pathogens social behaviors offer numerous advantages and studies of social interactions in bacteria have revolutionized our understanding of microbial pathogenesis. We hypothesize that social behavior in T. brucei provides similar advantages for trypanosome development and pathogenesis and that systems used by T. brucei for cell-cell signaling in social motility overlap with systems used to sense and respond to host signals. The current proposal will identify genes and mechanisms underlying social behavior in trypanosomes. Given the widespread social interactions among other microbes we expect our studies to have broad relevance among parasitic protozoa. PUBLIC HEALTH RELEVANCE: African trypanosomes and related parasites are the source of morbidity and mortality in several million people worldwide and diseases caused by these pathogens are among the world's most neglected diseases. The proposed project will identify genes and mechanisms required for social behavior in trypanosomes. In bacterial pathogens, social interactions have profound influences on disease pathogenesis, but this paradigm has only recently been applied to parasites and we therefore expect to uncover novel concepts and mechanisms that apply broadly to other parasitic infections.