Cell Migration in Tuberculosis Infection

结核感染中的细胞迁移

• 批准号: 7391536
• 负责人: John R. Chan
• 金额: $ 38.73万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7391536
• 关键词: Acute; Anti-Inflammatory Agents; Anti-inflammatory; Antimycobacterial Agents; Area; Attention; Bacillus (bacterium); Biological; CXCR3 gene; Cell Adhesion Molecules; Cells; Cessation of life; Chronic Phase; Collection; Complex; Disease; Equilibrium; Funding; Goals; Granuloma; Granulomatous; Hand; Human; Immune; Immune response; Immune system; Immunity; Immunocompetent; Immunologic Factors; Immunologics; In Vitro; Individual; Infection; Infection Control; Infection prevention; Inflammatory; Investigation; Kinetics; Knock-out; Life; Ligands; Literature; Lung; Modeling; Mus; Mycobacterium tuberculosis; Numbers; Organism; Pathogenesis; Pathologic; Pathology; Persons; Phagocytes; Phase; Play; Risk; Role; Signal Transduction; Site; Structure; Testing; Time; Tuberculosis; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; base; cell motility; cell type; chemokine; chemokine receptor; disease transmission; follow-up; human TNF protein; immunopathology; in vivo; macrophage; migration; mycobacterial; novel; pathogen; programs; response; transmission process; vigilance

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis is a remarkably successful human pathogen, and has coexisted with humans for thousands of years. Although only -10% of infected individuals develop active tuberculosis, the shear number of latently infected persons results in 8 million new cases of TB and 2 million deaths worldwide every year. The immune response to M. tuberculosis proceeds slowly but culminates in a granuloma. This collection of immune cells not only functions to focus the immune response on the area of infected macrophages, but also serves as an immunologic barrier to dissemination of the infection throughout the lungs. Interestingly, a proportion of M. tuberculosis bacilli can survive and persist in the granuloma, and this structure appears to greatly facilitate transmission of disease by causing pathology in the lungs. Thus, the granuloma is the intermediate goal for both the host and the pathogen. This makes identifying the "protective" and "pathologic" features of the immune response to M. tuberculosis complex and difficult. As a collaborative project for the past 14 years, we have studied the signals and factors that result in cell migration and granuloma formation in tuberculosis, with particular attention paid to tumor necrosis factor (TNF). TNF is a master regulator of the granulomatous response and of many aspects of the immune system. Humans treated with TNF neutralizing agents have a substantially increased risk of tuberculosis. We propose to follow up on our previous findings to study aspects of TNF and cell migration in the murine model of tuberculosis. Specifically, we will identify mechanisms the pro- and anti-inflammatory mechanisms related to TNF in M. tuberculosis infection (Aim 1), generate novel inducible knockout strains to determine which cell types are responsible for controlling the various phases of infection (Aim 2), and follow up on surprising findings that the chemokine receptor CXCR3 may impair the ability of the host to control M. tuberculosis infection (Aim 3). Our goal is a better understanding of the interplay between host and pathogen during infection, to identify strategies to eliminate persistent organisms.

描述（由申请人提供）：结核分枝杆菌是一种非常成功的人类病原体，已经与人类共存了数千年。尽管只有-10％的受感染者发生活跃的结核病，但潜在感染者的剪切数量每年导致800万例新的结核病和200万例死亡。对结核分枝杆菌的免疫反应缓慢地进行，但最终在肉芽肿中达到顶点。这种免疫细胞的集合不仅功能将免疫反应集中在感染巨噬细胞的区域上，而且还充当了整个肺部感染传播感染的免疫障碍。有趣的是，结核分枝杆菌的比例可以在肉芽肿中存活并持续存在，这种结构似乎通过在肺部引起病理学而极大地促进了疾病的传播。因此，肉芽瘤是宿主和病原体的中间目标。这使得识别对结核分枝杆菌复合物和困难的免疫反应的“保护性”和“病理”特征。作为过去14年的协作项目，我们研究了导致结核病细胞迁移和肉芽肿的信号和因素，并特别注意肿瘤坏死因子（TNF）。 TNF是肉芽肿反应和免疫系统许多方面的主要调节剂。用TNF中和剂处理的人类患有结核病的风险大大增加。我们建议跟进我们以前的发现，以研究结核鼠模型中TNF和细胞迁移的方面。具体而言，我们将确定与结核分枝杆菌感染中与TNF相关的促和抗炎机制的机制（AIM 1），生成新型的诱导型敲除菌株，以确定哪些细胞类型负责控制感染的各种阶段（AIM 2），并跟进了令人惊讶的发现，即趋于趋化因子受体CXCR3可能会受到危险感染的IMM。我们的目标是更好地理解感染过程中宿主与病原体之间的相互作用，以确定消除持续生物的策略。