Identification of factors contributing to group behavior in African Trypanosomes

非洲锥虫群体行为影响因素的鉴定

• 批准号: 8129845
• 负责人: Miguel Augusto Lopez
• 金额: $ 3.31万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8129845
• 关键词: Accounting; Africa South of the Sahara; African; African Trypanosomiasis; Animal Model; Bacteria; Behavior; Biology; Bite; Blood Circulation; Cattle; Cells; Communities; Development; Disease; Drug Delivery Systems; Drug resistance; Economic Development; Environment; Exhibits; Genes; Genetic; Genetic Screening; Goals; Host Defense; Human; Individual; Infection; Insecta; Knock-out; Libraries; Life; Life Cycle Stages; Life Style; Mastigophora; Microbe; Microbial Biofilms; Microbial Physiology; Morbidity - disease rate; Nutrient; Parasites; Parasitic infection; Pathogenesis; Pharmaceutical Preparations; Protozoa; RNA Interference; Reporting; Risk; Role; Sepharose; Series; Signal Transduction; Social Behavior; Social Interaction; Solid; Source; Staging; Stimulus; Surface; Suspension Culture; System; Testing; Tissues; Trypanosoma; Trypanosoma brucei brucei; Tsetse Flies; Vaccines; cell motility; human mortality; in vivo; intercellular communication; invertebrate host; microbial; migration; mortality; mutant; nagana; neglect; novel; pathogen; population movement; social; vector

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.

描述（由申请方提供）：布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长角线虫病的病原体。昏睡病是一种在撒哈拉以南非洲重新出现的疾病，约有6000万人生活在感染的风险中。昏睡病如果未经治疗和没有疫苗是致命的。目前的药物陈旧、有毒、难以服用，抗药性的发展加剧了这种情况。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。T.布氏杆菌通过受感染的采采蝇媒介的叮咬传播到哺乳动物宿主的血液中。在两个寄主中，T.布氏杆菌与组织表面紧密接触，并表现出对感应和信号传导的隐含需求，以引导寄生虫迁移和分化。这一点在采采蝇身上尤为明显。目前，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T.当在半固体琼脂糖平板上培养时，布鲁氏菌参与社会行为。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交流以协调种群的运动。T.布氏杆菌揭示了原生动物行为的复杂性和合作性，这是以前没有认识到的。在其他微生物病原体中，社会行为提供了许多优势，细菌中社会相互作用的研究彻底改变了我们对微生物致病机理的理解。我们假设T.布氏锥虫对锥虫的发育和发病机制提供了类似的优势，而T.布鲁氏菌在社会运动中的细胞-细胞信号传导与用于感知和响应宿主信号的系统重叠。目前的提议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相互作用，我们希望我们的研究在寄生原生动物中具有广泛的相关性。 公共卫生关系：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着深远的影响，但这种模式最近才被应用于寄生虫，因此我们希望发现广泛适用于其他寄生虫感染的新概念和机制。