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。虽然只有-10%的感染者发展为活动性结核病，但潜伏感染者的数量每年导致全世界800万新发结核病病例和200万人死亡。对结核分枝杆菌的免疫反应进展缓慢，但最终形成肉芽肿。这些免疫细胞集合不仅可以将免疫反应集中在感染巨噬细胞的区域，而且还可以作为整个肺部感染传播的免疫屏障。有趣的是，一部分结核分枝杆菌可以在肉芽肿中存活并持续存在，这种结构似乎通过引起肺部病变极大地促进了疾病的传播。因此，肉芽肿是宿主和病原体的中间目标。这使得确定对结核分枝杆菌免疫反应的“保护性”和“病理性”特征变得复杂和困难。作为过去14年的合作项目，我们研究了导致结核细胞迁移和肉芽肿形成的信号和因素，特别关注肿瘤坏死因子（TNF）。TNF是肉芽肿反应和免疫系统许多方面的主要调节因子。用肿瘤坏死因子中和剂治疗的人患结核病的风险大大增加。我们建议在之前的研究基础上进一步研究肿瘤坏死因子和细胞迁移在小鼠结核模型中的作用。具体来说，我们将确定结核分枝杆菌感染中与TNF相关的促炎和抗炎机制（Aim 1），产生新的可诱导敲除菌株，以确定哪些细胞类型负责控制感染的各个阶段（Aim 2），并追踪趋化因子受体CXCR3可能损害宿主控制结核分枝杆菌感染的能力（Aim 3）的惊人发现。我们的目标是在感染过程中更好地了解宿主和病原体之间的相互作用，以确定消除持久性生物体的策略。