Functional Studies of Toxoplasma gondii AMA1 and AMA2

弓形虫 AMA1 和 AMA2 的功能研究

• 批准号: 7218063
• 负责人: GARY E WARD
• 金额: $ 36.03万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7218063
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Biological Assay; Cells; Chemotherapy-Oncologic Procedure; Cytolysis; Development; Disease; Fetus; Gene Expression; Genes; Genome; Hodgkin Disease; Homologous Gene; Human; Immunocompromised Host; Immunosuppressive Agents; Infection; Infection Control; Invaded; Lead; Life; Malaria; Malaria Vaccines; Mediating; Membrane Proteins; Mining; Modeling; Mutation; Parasites; Pathogenesis; Pathogenicity; Persons; Plasmodium; Plasmodium falciparum; Play; Process; Protein Family; Proteins; Proteolytic Processing; Role; Role playing therapy; Site; Structure; Surface; System; Thinking; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; Transgenic Organisms; Vaccine Design; Virulence; Work; apical membrane; base; in vivo; insight; interest; novel vaccines; parasite invasion; pathogen; prevent; secretion process

DESCRIPTION (provided by the applicant): Apicomplexan parasites such as Toxoplasma gondii, the causative agent of toxoplasmosis, and Plasmodium falciparum, the causative agent of severe human malaria, are obligate intracellular pathogens. Repeated cycles of host cell invasion, parasite multiplication and host cell lysis are central to the pathogenicity of these parasites, yet little is known about the mechanisms of host cell invasion or the parasite proteins that mediate the process. One protein that has been the focus of intense interest is AMA1. AMA1 is conserved among apicomplexans, and Plasmodium AMA1 is a leading malaria vaccine candidate. AMA1 is released onto the parasite surface during interaction with host cells, where it is thought to play an essential - though still undefined - role in host cell invasion. The T. gondii homolog of AMA1 (TgAMAl) has recently been identified, and a new system for conditional gene expression in T. gondii has enabled the creation of a parasite line in which expression of TgAMAl can be experimentally manipulated. A decrease in TgAMAl expression in these parasites causes a significant decrease in their invasiveness. The conditional knockdown parasites provide an unprecedented opportunity to study the function of a model AMA1 protein. Specific Aim 1 will use the conditional knockdown parasites and the wealth of assays available in T. gondii to deter mine the specific role played by TgAMAl in invasion. Specific Aim 2 will explore the functional significance of proteolytic cleavage and release of TgAMAl from the parasite surface during invasion. Specific Aim 3 will characterize and determine the function of TgAMA2, an AMAl-like sequence that is also expressed in T. gondii tachyzoites. T. gondii causes life-threatening disease in the congenitally-infected fetus and in immunocompromised persons, including those with AIDS or Hodgkins' disease, and those undergoing immunosuppressive or cancer chemotherapy. Given the apparent importance of AMA1 in invasion and the central role invasion plays in pathogenesis, a greater understanding of the function of AMA1 and AMA1-related proteins will likely contribute to the development of new vaccine-based or chemotherapeutic approaches to preventing or controlling infection by T. gondii and other apicomplexan parasites.

描述（由申请人提供）：Apicomplexan寄生虫，例如弓形虫弓形虫，弓形虫病的病因，而恶性疟原虫是严重的人类疟疾的病原体，是义务的细胞内病原体。宿主细胞侵袭，寄生虫繁殖和宿主细胞裂解的重复周期是这些致病性的核心 寄生虫对宿主细胞侵袭或介导该过程的寄生虫蛋白的机制知之甚少。一种一直是强烈兴趣的焦点的蛋白质是AMA1。 AMA1在Apicomplexans中是保守的，疟原虫AMA1是领先的疟疾疫苗候选者。在与宿主细胞相互作用期间，AMA1被释放到寄生虫表面上，在该宿主细胞中，人们认为在宿主细胞侵袭中起着必不可少的作用（尽管仍然不确定）。最近已经鉴定出了AMA1（TGAMAL）的T. gondii同源物，并且在T. gondii中有条件基因表达的新系统已使寄生虫线创建，其中可以通过实验进行tgamal的表达。这些寄生虫中tgamal表达的降低会导致其侵入性显着降低。有条件的敲低寄生虫为研究模型AMA1蛋白的功能提供了前所未有的机会。具体的目标1将使用条件敲低的寄生虫和T. gondii可用的大量测定法，以阻止tgamal在入侵中发挥的特定作用。特定的目标2将探索蛋白水解裂解和在入侵期间从寄生虫表面释放的功能意义。特定的目标3将表征并确定tgama2的功能，tgama2是一种类似伴奏的序列，在gondii tachyzoites中也表达。 T. gondii会引起先天感染的胎儿和免疫功能低下的人，包括患有艾滋病或霍奇金斯疾病的人，以及接受免疫抑制或癌症化学疗法的人。鉴于AMA1在侵袭中显然重要的重要性，并且在发病机理中的核心作用发挥了对AMA1和AMA1相关蛋白的功能的更多了解，可能有助于开发新的基于疫苗的或化学治疗方法，以防止T. Gondii和其他Apicomplexan Parasites预防或控制感染。