GLOBAL ANALYSIS OF THE HOST CELL RESPONSE TO TOXOPLASMA GONDII INFECTION IN ASTR

ASTR 中宿主细胞对弓形虫感染反应的整体分析

• 批准号: 8359571
• 负责人: SANDRA K HALONEN
• 金额: $ 18.48万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8359571
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Animals; Apoptosis; Astrocytes; Biochemical; Brain; Cancer Patient; Cells; Cellular Structures; Development; Disease; Effector Cell; Encephalitis; Environment; Funding; Genetic; Genetic Transcription; Grant; Growth; Growth and Development function; Host Defense; Host Defense Mechanism; Immunocompromised Host; In Vitro; Individual; Infection; Interferon Type II; Intervention; Mediating; Modeling; Mus; National Center for Research Resources; Neuraxis; Outcome; Parasites; Pathway interactions; Patients; Phenotype; Play; Post-Translational Protein Processing; Principal Investigator; Proteins; Proteomics; Regulation; Research; Research Infrastructure; Resistance; Resources; Role; Source; Systems Biology; Tissues; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; Transplant Recipients; United States National Institutes of Health; Virulent; War; cell type; chemotherapy; clinically relevant; cost; cytokine; latent infection; mRNA Expression; macrophage; mutant; pathogen; protein expression; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Toxoplasma gondii is a major opportunistic pathogen of the central nervous system, that causes significant disease in AIDS patients and other immunocompromised individuals, such as transplant recipients and cancer patients undergoing chemotherapy. In these individuals infection is due to reactivation of a latent infection in the brain and results in severe and often fatal necrotizing encephalitis. Cytokines play an important role in the regulation of T. gondii in the central nervous system and interferon-gamma (IFNgamma) is the main cytokine controlling replication of T. gondii in the brain and in other tissues. The mechanism of IFNgamma inhibition in murine astrocytes and macrophages is partially dependent upon the IFNv-induced response protein, IGTP. Natural host-defense mechanisms are influenced by the parasite, which is known to substantially alter host cell transcription, and there is clear evidence for active parasite intervention in pathways affecting host cell apoptosis and the cytokine response. The biochemical outcome of this tug-of-war influences the establishment of a host cell environment that either supports or is hostile to parasite growth and development. The host cell components and the factors by which the parasite manipulates the host cell environment are not understood, but these mechanisms appear to vary extensively between strains that express a wide range of growth and virulent phenotypes. Astrocytes are an important host cell for T. gondii in the brain and an important IFNgamma-activated effector cell, mediating resistance to T. gondii in the brain. As such, the astrocyte model provides an opportunity to understand host-defense and parasite survival mechanisms in a clinically relevant cell type. We will take a comprehensive approach to characterize the changes in host mRNA and protein expression and protein post-translational modification that occur in primary astrocytes obtained from animals that are exposed in vitro to Toxoplasma infection, under conditions where protection is afforded by IFNgamma stimulation in this project. We will define the IFNgamma response in astrocytes and explore how these host cell changes are altered by parasites of distinct genetic lineage and virulent phenotypes. The three specific aims of this proposal are: 1) Transcriptional analysis of the host cell response to T. gondii infection in IFNgamma stimulated vs. unstimulated astrocytes, 2) Proteomic analysis of the host cell response to T. gondii infection in IFNgamma stimulated vs. unstimulated astrocytes and 3) Development of a screen for T. gondii survival mutants subjected to IFNgamma stimulation in astrocytes.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 弓形虫Gondii是中枢神经系统的主要机会病原体，它在艾滋病患者和其他免疫功能低下的个体中引起重大疾病，例如移植受者和接受化学疗法的癌症患者。在这些个体中，感染是由于大脑中潜在感染的重新激活，并导致严重且经常致命的坏死性脑炎。细胞因子在中枢神经系统中的T. gondii和干扰素 - γ（Ifngamma）中起着重要作用，是控制大脑和其他组织中T. gondii复制的主要细胞因子。鼠星形细胞和巨噬细胞中IFNGAMMA抑制的机制部分取决于IFNV诱导的反应蛋白IGTP。自然宿主防御机制受寄生虫的影响，寄生虫已知会大大改变宿主细胞转录，并且有明确的证据表明，在影响宿主细胞凋亡和细胞因子反应的途径中有效的寄生虫干预。这次拔河的生化结果影响了支持或敌对寄生虫生长和发育的宿主细胞环境的建立。宿主细胞成分以及寄生虫操纵宿主细胞环境的因素尚不清楚，但是这些机制似乎在表达广泛生长和强大表型的菌株之间差异很大。星形胶质细胞是大脑中gondii的重要宿主细胞，也是重要的IFNGAMMA激活效应细胞，可介导对大脑中gondii的抗性。因此，星形胶质细胞模型为了解临床相关细胞类型中的宿主防御和寄生虫生存机制提供了机会。我们将采用一种全面的方法来表征宿主mRNA和蛋白质表达和蛋白质后翻译后修饰的变化，这些修饰是在该项目中受ifngamma刺激提供的保护下，从体外暴露于体外暴露于体外暴露于体外暴露于弓形虫感染的动物中。我们将定义星形胶质细胞中的IFNGAMMA反应，并探讨这些宿主细胞变化如何通过不同的遗传谱系和有毒表型的寄生虫改变。 The three specific aims of this proposal are: 1) Transcriptional analysis of the host cell response to T. gondii infection in IFNgamma stimulated vs. unstimulated astrocytes, 2) Proteomic analysis of the host cell response to T. gondii infection in IFNgamma stimulated vs. unstimulated astrocytes and 3) Development of a screen for T. gondii survival mutants subjected to IFNgamma星形胶质细胞的刺激。