Intracellular Pathogens and Innate Immunity

细胞内病原体和先天免疫

• 批准号: 7177234
• 负责人: DANIEL A PORTNOY
• 金额: $ 5.76万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7177234
• 关键词: immunity; macrophage

Macrophages play pivotal roles in the biology of infectious diseases as hosts to intracellular pathogens, mediators of inflammation, and orchestrators of acquired immunity. It is no surprise that among most of the NIAID priority pathogens, macrophages are critical to the outcome of infection. A central hypothesis of this Program Project is that intracellular pathogens manipulate the response of macrophages to promote disease. Furthermore, the transcriptional response of macrophages to infection serves as a fundamental read-out of the overall response. The purpose of this Program Project is to use a taxonomically and structurally distinct and clinically relevant panel of intracellular pathogens to establish the transcription profile of macrophages in response to microbial infection using a newly developed and novel microarray containing probes for all known mouse genes (Core B). This transcriptional profile will then serve as a benchmark to understand how the host response is manipulated by each pathogen. By profiling the transcriptional response of macrophages to microbial mutants that are defective in their pathogenic interactions with macrophages, we will learn how pathogens manipulate host cells to promote infection. By using macrophages derived from knockout mice in combination with microbial mutants, we will identify the pathways of innate immune recognition that determine the host response and how pathogens can manipulate these pathways for their benefit. These studies will illuminate essential and conserved pathways of macrophage control of innate immunity, thereby providing potential targets of therapeutic intervention as well as pathogenic signatures that will serve to uncover basic mechanisms of microbial pathogenesis and host response. The specific Aims are to (1) Identify microbial determinants of pathogenesis that affect macrophage innate immune responses in Listeria monocytogenes, Francisella tularensis, Mycobacterium tuberculosis and Histoplasma capsulatum; (2) Characterize the intracellular replication and trafficking of microbial mutants in bone marrow-derived macrophages. (3) Characterize host gene expression profiles using custom synthesized DNA microarrays in response to wild-type and mutant microbial pathogens in macrophages from wild-type and mutant mice.

巨噬细胞在传染病的生物学中起关键作用，作为细胞内病原体的宿主，炎症的介体以及获得免疫的序曲。毫不奇怪的是，在大多数NIAID优先病原体中，巨噬细胞对感染的结果至关重要。该计划项目的一个核心假设是，细胞内病原体操纵巨噬细胞对促进疾病的反应。此外，巨噬细胞对感染的转录反应是整体反应的基本读数。 该计划项目的目的是使用细胞内病原体的分类学和结构上不同和临床相关的面板，以使用新发达的和新的微阵列含有所有已知小鼠基因的探针（Core B）来建立巨噬细胞的转录谱，以应对微生物感染。然后，此转录曲线将作为基准，以了解每种病原体如何操纵宿主反应。通过分析巨噬细胞对微生物突变体的转录反应，这些突变体在其与巨噬细胞的致病相互作用中有缺陷，我们将学习病原体如何操纵宿主细胞以促进感染。通过将源自基因敲除小鼠与微生物突变体结合使用的巨噬细胞，我们将确定确定宿主反应的先天免疫识别途径，以及病原体如何为它们的益处操纵这些途径。这些研究将阐明对先天免疫的巨噬细胞控制的必要和保守途径，从而提供治疗干预的潜在靶标，以及致病性特征，这些靶标将有助于发现微生物发病机理和宿主反应的基本机制。具体目的是（1）确定影响巨噬细胞单核细胞增生液，francisella tularensis，tobleculculculosis和Histoplasma capsulatum中巨噬细胞免疫反应的发病机理的微生物决定因素； （2）表征微生物突变体在骨髓来源的巨噬细胞中的细胞内复制和运输。 （3）使用自定义合成的DNA微阵列表征宿主基因表达谱，以响应野生型和突变小鼠的巨噬细胞中的野生型和突变微生物病原体。