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UPTAKE OF HOST CELL CHOLESTEROL BY T GONDII

弓形虫对宿主细胞胆固醇的摄取

基本信息

批准号：
6752952
负责人：
KEITH Alan JOINER
金额：
$ 30.1万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-07-01 至 2006-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6752952
关键词：
Toxoplasma gondii cholesterol endocytosis host organism interaction intracellular membranes intracellular parasitism lipid transport low density lipoprotein receptor membrane structure microorganism growth microorganism metabolism nutrient bioavailability nutrition related tag opportunistic infections tissue /cell culture

项目摘要

DESCRIPTION (from applicant's abstract): Toxoplasma gondii is an obligate intracellular parasite, which is capable of invading and replicating within all nucleated cells. Toxoplasmosis, particularly involving the brain, is a major source of morbidity and mortality in the Acquired Immune Deficiency Syndrome. The vacuole membrane surrounding the intracellular parasite contains a functional pore, which allows diffusion of small nutrients from the host cell into the vacuolar space surrounding the parasite. However, essentially nothing is known about macromolecules of host cell origin required for parasite growth, nor of mechanisms for parasite acquisition of these nutrients. We have demonstrated that intracellular T. gondii tachyzoites efficiently acquire and sequester host cell cholesterol internalized into cells through the host cell LDL receptor pathway. Viable parasites are required for this process, potentially implicating a secreted parasite sterol binding protein. Providing excess cholesterol to infected cells accelerates T. gondii growth, suggesting that cholesterol is limiting for parasite growth. T. gondii induces an increase in LDL internalization in infected host cells, possibly by activating host cell regulatory mechanisms of cholesterol homeostasis. These are all completely unexpected findings for a parasite, which resides in a vacuole, which does not fuse with organelles of the host endocytic cascade. To pursue the above observations, the mechanism by which the parasite regulates expression of host genes involved in sterol uptake and biosynthesis will be determined. Secreted parasite proteins, which participate in cholesterol acquisition from the host cell will be identified. Endocytic traffic in the parasite will be perturbed using pharmacologic and molecular manipulations, and effects on cholesterol uptake and delivery to parasite organelles will be assessed. These experiments are important because they elucidate the mechanisms of transport of an essential nutrient cholesterol - sequentially from the host cell to the PVM and PV, then across the parasite plasma membrane an ultimately to parasite organelles. Simultaneously, they define the contribution of the T. gondii endocytic pathway to macromolecule uptake, and open the possibility that this pathway can be used for therapeutic advantage in T. gondii and potentially in other Apicomplexan parasites, most notably Cryptosporidium parvum.

描述(摘自申请者摘要)：弓形虫是必备的细胞内寄生虫，它能够入侵并在所有有核细胞。弓形虫病，尤其是累及大脑的，是一种主要的获得性免疫缺陷综合征的发病率和死亡率来源。细胞内寄生虫周围的液泡膜包含一个功能孔，允许从宿主细胞扩散少量营养物质进入寄生虫周围的液泡空间。然而，基本上什么都没有已知寄生虫生长所需的宿主细胞来源的大分子，也不了解寄生虫获取这些营养物质的机制。我们有证明了细胞内弓形虫速殖子有效地获取和隔离宿主细胞胆固醇通过宿主细胞内化到细胞内低密度脂蛋白受体途径。这一过程需要有活性的寄生虫，可能与一种分泌型寄生虫类固醇结合蛋白有关。提供感染细胞中过量的胆固醇会加速弓形虫的生长，这表明胆固醇限制了寄生虫的生长。弓形虫的诱生作用在被感染的宿主细胞中内化低密度脂蛋白，可能是通过激活宿主细胞胆固醇稳态的调节机制。这些都是完全对一种寄生虫的意外发现，这种寄生虫驻留在液泡中，而不是与宿主内细胞级联的细胞器融合。追求上述目标观察，寄生虫调节寄主表达的机制参与类固醇摄取和生物合成的基因将被确定。秘而不宣参与从宿主获取胆固醇的寄生虫蛋白细胞将被识别。寄生虫体内的胞内交通会受到干扰使用药物和分子操作，以及对胆固醇的影响将评估对寄生虫细胞器的摄取和输送。这些实验是很重要的，因为它们阐明了一种必需的营养胆固醇-从宿主细胞到PVM的顺序和 PV，然后穿过寄生虫的质膜，最终到达寄生虫细胞器。同时，它们定义了弓形虫的贡献大分子摄取的内吞途径，并开启了这一可能性途径可用于弓形虫的治疗优势，并有可能在其他顶端复合体寄生虫，最著名的是微小隐孢子虫。