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Toxoplasma endocytosis of host cytoplasm

弓形虫对宿主细胞质的内吞作用

基本信息

批准号：
8445544
负责人：
Vernon Bruce Carruthers
金额：
$ 19.44万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-15 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8445544
关键词：
Acute Antibodies Attenuated Binding Biogenesis Biological Assay Brain Cathepsin L Cells Complex Cytoplasm Cytoplasmic Granules Cytosol Dendritic Cells Destinations Dominant-Negative Mutation Endocytosis Ensure Eye Eye diseases Goals Growth Guanosine Triphosphate Phosphohydrolases Heart Host Defense Human Immune Immune response Immunity Individual Infant Infection Interferon Type II Life Life Style Luciferases Lung Membrane Mus Natural Immunity Parasite Control Parasites Pathway interactions Peptide Hydrolases Phosphorylation Proteins Proteolysis Recruitment Activity Reporter Research Role Severities Shelter facility Site Staging System Testing Toxoplasma Toxoplasma gondii Toxoplasmosis Tubular formation Vacuole Virulence Work attenuation base cytokine immune clearance killings lymph nodes macrophage novel pathogen public health relevance rhoptry uptake

项目摘要

DESCRIPTION (provided by applicant): Innate immune defenses help restrict growth of the protozoan pathogen Toxoplasma gondii, but their efficacy is offset by parasite counter defenses. For example, infected macrophages attempt to destroy the parasite by expressing immunity-related GTPases (IRGs) that load onto and dismantle the parasitophorous membrane, but the parasite thwarts this by phosphorylating Irg proteins to diminish their activity. Since phosphorylation is a reversible, and therefore temporary, we hypothesize that T. gondii additionally eliminates these host effector proteins permanently by internalizing them into its endocytic system. Our recent unexpected finding that the parasite readily internalizes a reporter protein expressed in the host cytosol supports this hypothesis. Further, the reporter protein is most abundantly seen in protease-deficient parasites, suggesting that internalized host proteins are normally digested in the parasite endocytic system. Also, parasites deficient in the biogenesis of tubular membranes within the parasitophorous vacuole are unable to efficiently internalize the reporter protein, indicating that the tubular membranes are required for uptake. These deficient parasites are also highly susceptible to killing by activated macrophages. The specific aims are to: (1) confirm the parasite endocytic system as the destination of internalized proteins; and (2) show that Toxoplasma uses the intravacuolar network of tubular membranes to internalize IRGs for destruction in its endolysosomal system. We expect to show that the parasite eliminates IRGs by endocytosis and degradation as an immune evasion strategy. The work is anticipated to open exciting new opportunities to diminish parasite intracellular survival during infection.

描述（由申请人提供）：先天免疫防御有助于限制原生动物病原体弓形虫的生长，但其功效被寄生虫的反防御抵消。例如，受感染的巨噬细胞试图通过表达免疫相关的GTP酶（IRG）来破坏寄生虫，这些GTP酶装载并拆除寄生虫膜，但寄生虫通过磷酸化Irg蛋白质以降低其活性来阻止这一点。由于磷酸化是可逆的，因此是暂时的，我们假设T。弓形虫还通过将这些宿主效应蛋白内化到其内吞系统中而永久地消除这些宿主效应蛋白。我们最近意外的发现，寄生虫很容易内化宿主胞质中表达的报告蛋白支持这一假设。此外，报告蛋白是最丰富的蛋白酶缺陷型寄生虫，这表明内化的宿主蛋白通常在寄生虫内吞系统消化。此外，寄生虫缺乏在寄生虫液泡内的管状膜的生物发生是无法有效地内化的报告蛋白，这表明需要的管状膜的摄取。这些缺陷型寄生虫也极易被活化的巨噬细胞杀死。具体目标是：（1）证实寄生虫内吞系统是内化蛋白的目的地;（2）表明弓形虫使用管状膜的液泡内网络内化IRG，以破坏其内溶酶体系统。我们希望表明，寄生虫消除IRGs的内吞作用和降解作为一种免疫逃避策略。这项工作有望为减少寄生虫在感染过程中的细胞内存活开辟令人兴奋的新机会。