Influence of the Host Cell Molecular Environment on Toxoplasma Development

宿主细胞分子环境对弓形虫发育的影响

• 批准号: 7494409
• 负责人: JAY R RADKE
• 金额: $ 21.38万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2010-02-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7494409
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; Acquired Immunodeficiency Syndrome; Animals; Apicomplexa; Binding; Blood; Cells; Chronic; Clinical; Consumption; Cues; Cyst; Development; Disease; Elements; Environment; Epidemic; Family Felidae; Future; Gene Expression; Genes; Genetic; Germ Cells; Growth; Human; Indium; Infection; Life; Livestock; Lytic; Mediating; Messenger RNA; Molecular; Muscle; N-methylpiperidine; Oocysts; Organ Transplantation; Parasites; Pathogenesis; Patients; Phenotype; Play; Population; Predisposition; Proliferating; Proteins; Public Health; Pyrroles; Recrudescences; Resistance; Role; Signal Transduction; Soil; Source; Staging; Structure; Testing; Tissues; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; Water; base; brain cell; cell division autoantigen-1; chemotherapy; clinically relevant; genetic element; human subject; pathogen; prenatal; pyridine; research study; resistance factors; transmission process

DESCRIPTION (provided by applicant): Toxoplasma gondii is a zoonotic protozoan that infects an estimated 1.5 million human subjects annually, and infection can be dangerous to the unborn, to patients undergoing chemotherapy or organ transplant, and to people with AIDS. Bradyzoite development is responsible for permanent infection and recrudescence to the lytic tachyzoite stage underlies the pathogenesis of clinical toxoplasmosis. The molecular basis for specific host-parasite interaction leading to bradyzoite development is mostly unknown, but evidence suggests that preferential development in long-lived, terminally differentiated cells like muscle and select cells of the brain can be dictated by the interaction of distinct, definable host- and parasite-specific factors. We have demonstrated treatment of the host cell with a trisubstituted pyrrole, designated Compound 1, induces new host cell gene expression and early bradyzoite development. One host mRNA expressed in the Compound 1-altered cell, called cell division autoantigen 1 (CDA1), is able to induce parasite development when over-expressed in the infected host cell alone. Our hypothesis is that increased CDA1 is one part of a molecular environment in the host that 'signals', or can be 'acted on' by, the parasite to initiate bradyzoite development. The molecular elements of this altered environment and the host- or parasite-specific molecules pertinent to induced development will have significant implications for understanding the pathogenesis of chronic Toxoplasma infection. To identify these key molecules and provide a basis for future experiments to understand the relevant interactions leading to natural bradyzoite development in the animal, we will (1) We will complete structure function studies to identify sequence elements in the CDA1 protein critical to induction of bradyzoite development and (2) identify the genetic elements that underlie parasite susceptibility to the Compound 1-altered host cell environment. PUBLIC HEALTH RELEVANCE Toxoplasma is a common opportunistic pathogen in AIDS. We have found the parasite can take cues from the host cell to establish permanent infection. These studies will seek to characterize the host cell influence on development using both host- and parasite-specific approaches to understand key molecular interactions that influence the pathogenesis of infection and disease.

描述（由申请人提供）：刚地弓形虫是一种人畜共患病的原生动物，每年感染约150万人，感染对未出生的胎儿、接受化疗或器官移植的患者以及艾滋病患者都是危险的。慢殖子的发育是导致永久性感染和复发到溶速殖子阶段的原因，是临床弓形虫病发病机制的基础。导致慢殖子发育的特定宿主-寄生虫相互作用的分子基础大多是未知的，但有证据表明，长期存在的、终末分化的细胞（如肌肉和大脑的精选细胞）的优先发育可以由不同的、可定义的宿主和寄生虫特异性因素的相互作用决定。我们已经证明用三取代吡咯处理宿主细胞，命名为化合物1，诱导新的宿主细胞基因表达和早期慢殖子发育。在化合物1改变的细胞中表达的一种宿主mRNA，称为细胞分裂自身抗原1 (CDA1)，当在受感染的宿主细胞中过度表达时，能够诱导寄生虫的发育。我们的假设是，增加的CDA1是宿主分子环境的一部分，它“发出信号”，或者可以被寄生虫“作用”，以启动慢殖子的发育。这种环境改变的分子因素以及与诱导发育相关的宿主或寄生虫特异性分子将对理解慢性弓形虫感染的发病机制具有重要意义。为了确定这些关键分子，并为未来的实验提供基础，以了解导致动物天然慢殖子发育的相关相互作用，我们将(1)我们将完成结构功能研究，以确定CDA1蛋白中诱导慢殖子发育的关键序列元件；(2)确定寄生虫对化合物1改变的宿主细胞环境易感性的遗传元件。弓形虫是艾滋病中一种常见的机会致病菌。我们发现寄生虫可以从宿主细胞中获取线索，建立永久性感染。这些研究将试图利用宿主和寄生虫特异性方法来描述宿主细胞对发育的影响，以了解影响感染和疾病发病机制的关键分子相互作用。