IFN Immune Effector Mechanisms in Cerebral Toxoplasmosis

脑弓形虫病中的干扰素免疫效应机制

• 批准号: 6909477
• 负责人: SANDRA K HALONEN
• 金额: $ 19.15万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-15 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6909477
• 关键词: Toxoplasma gondii; astrocytes; bioterrorism /chemical warfare; cholesterol; endocytosis; endoplasmic reticulum; exocytosis; fluorescent dye /probe; gene expression; genetically modified animals; guanosinetriphosphatases; host organism interaction; immune response; immunofluorescence technique; interferon gamma; laboratory mouse; microarray technology; mitochondria; monoclonal antibody; nervous system infection; protein structure function; tissue /cell culture; toxoplasmosis; transmission electron microscopy; vesicle /vacuole

DESCRIPTION (provided by the applicant): Toxoplasma gondii is a ubiquitous intracellular protozoan parasite that is a major opportunistic infection in immunocompromised individuals, the cause of congenital toxoplasmosis in newborns and recently has been identified as a potential bioterrorism agent (list B). Cytokines play an important role in the regulation of T. gondii in the central nervous system. Interferon-gamma (IFN() is the main cytokine controlling replication of T. gondii in the brain. The investigator's previous studies defined that IFNgamma significantly inhibits the replication of T. gondii in astrocytes. The mechanism of IFNgamma in astrocytes was found to be independent of all of the known anti-Toxoplasma effector mechanisms. However, the investigator recently determined that IFNgamma mediated inhibition in astrocytes was reversed in astrocytes deficient in the GTP binding protein, IGTP (deltaIGTP). The function of IGTP is not known but it is thought to be involved in regulation of the vesicular trafficking pathway. Preliminary microarray studies of IFNgamma induced gene expression in astrocytes indicate that host cell cholesterol metabolism is altered in IFNgamma treated astrocytes. T. gondii has recently been shown to require cholesterol uptake from the host cell. Effects on lipid and cholesterol trafficking to the parasitophorous vacuole may be the mechanism of IFNgamma inhibition in astrocytes. As IFNgamma dependent mechanism(s) play a major role in controlling T. gondii in the brain, understanding these mechanism(s) remains an important challenge in understanding disease pathogenesis. In this project the mechanism(s) of IFNgamma induced inhibition in astrocytes will be investigated. The specific aims of this proposal are: 1) Identify the IFNgamma response genes in wild type and IGTP knockout (deltaIGTP) astrocytes via microarray analysis, 2) Characterize the effect of IFNgamma on the establishment of the parasitophorous vacuole in astrocytes and 3) Investigate the hypothesis that IFNgamma inhibition is mediated by affecting vesicular trafficking and/or cholesterol trafficking to the parasitophorous vacuole and that IGTP is involved in regulating this trafficking.

描述（由申请人提供）：弓形虫Gondii是一种无处不在的细胞内原生动物寄生虫，是免疫强化个体中的主要机会感染，是新生儿先天性弓形虫病的原因，最近被确定为潜在的生物恐怖剂（列表B）。细胞因子在中枢神经系统中的弓形虫调节中起着重要作用。干扰素伽玛（IFN（IFN（）是控制大脑中巨细胞的主要细胞因子复制。但是，在所有已知的抗毒性效应机制中，研究人员最近确定IFNGAMMA介导的星形胶质细胞抑制作用在GTP结合蛋白IGTP（deltaigtp）中的星形胶质细胞中逆转。涉及囊泡运输途径的调节。对寄生虫液泡的脂质和胆固醇运输的影响可能是星形胶质细胞中Ifngamma抑制作用的机制。由于IFNGAMMA依赖性机制在控制大脑中的T. gondii中起着重要作用，因此了解这些机制仍然是理解疾病发病机理的重要挑战。在该项目中，将研究IFNGAMMA诱导的星形胶质细胞抑制作用的机制。该提案的具体目的是：1）通过微阵列分析确定野生类型和IGTP敲除（Deltaigtp）星形胶质细胞中的IFNGAMMA反应基因，2）表征IFNGAMMA对建立寄生虫液泡在星形胶质细胞中的影响，并研究3）。假设IFNGAMMA抑制是通过影响囊泡贩运和/或胆固醇运输到寄生虫液泡来介导的，并且IGTP参与调节这种贩运。