Cell Migration in Tuberculosis Infection

结核感染中的细胞迁移

• 批准号: 7285719
• 负责人: John R. Chan
• 金额: $ 40.39万
• 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/7285719
• 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(申请人提供)：结核分枝杆菌是一种非常成功的人类病原体，数千年来一直与人类共存。虽然只有10%的感染者患上活动性结核病，但潜伏感染人数的大幅增加每年导致全球800万新结核病病例和200万人死亡。对结核分枝杆菌的免疫反应进展缓慢，但最终导致肉芽肿。这种免疫细胞的集合不仅将免疫反应集中在受感染的巨噬细胞区域，而且还起到了免疫屏障的作用，阻止感染在整个肺部传播。有趣的是，一定比例的结核杆菌可以存活并存活在肉芽肿中，这种结构似乎极大地促进了疾病的传播，因为它导致了肺部的病理。因此，肉芽肿是宿主和病原体的中间目标。这使得识别结核分枝杆菌免疫反应的“保护性”和“病理性”特征变得复杂而困难。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，特别是肿瘤坏死因子(TNF)。肿瘤坏死因子是肉芽肿性反应和免疫系统许多方面的主要调节因子。接受肿瘤坏死因子中和剂治疗的人患结核病的风险大大增加。我们建议在先前发现的基础上，在小鼠结核病模型中研究肿瘤坏死因子和细胞迁移的各个方面。具体地说，我们将确定结核分枝杆菌感染中与肿瘤坏死因子相关的促炎和抗炎机制(目标1)，产生新的可诱导基因敲除菌株以确定哪些细胞类型负责控制感染的不同阶段(目标2)，并跟进趋化因子受体CXCR3可能损害宿主控制结核分支杆菌感染的能力(目标3)的令人惊讶的发现。我们的目标是更好地了解宿主和病原体在感染过程中的相互作用，确定消除持久性生物的策略。