Cell Migration in Tuberculosis Infection

结核感染中的细胞迁移

• 批准号: 6894704
• 负责人: John R. Chan
• 金额: $ 60.4万
• 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 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6894704
• 关键词: cell migration; cellular immunity; chemokine; chemokine receptor; granuloma; immunocytochemistry; laboratory mouse; laser capture microdissection; tuberculosis; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): The granuloma plays an important role in host defense against M. tuberculosis. The mechanisms that regulate the formation and maintenance of the tuberculous granuloma are, however, poorly understood. Chemokines and chemokine receptors play an essential role in cell migration in both physiological and pathophysiological states. Emerging evidence suggests a role for chemokine and chemokine receptors in regulating the granulomatous response during infection. M. tuberculosis has the ability to modulate chemokine and chemokine receptor expression in both in vitro and in vivo systems. Tumor necrosis factor-alpha (TNF-alpha) is essential for the control of tuberculosis, and is a potent regulator of chemokine expression and leukocyte trafficking. We have shown that neutralizing TNF-alpha in mice with persistent tuberculosis results in disease recrudescence associated with granuloma disorganization and diffuse cellular infiltration in the lungs. Based on these observations, we propose to test the hypotheses that: i) chemokines and chemokine receptors play an important role in orchestrating cell migration and granuloma formation in tuberculosis; and ii) TNF-alpha regulates the granulomatous response by directing the trafficking of immune cells at the site of infection via regulation of specific chemokines and chemokine receptors. Because of the importance of Type 1 T cells in host defense against M. tuberculosis, efforts will be focused on examining a subset of chemokines and receptors that can modulate migration of these T lymphocytes. Murine tuberculosis models, as well as immunohistochemical, laser microdissection, and realtime PCR techniques will be used to characterize the expression of these specific chemokines and receptors during tuberculous infection. Mice with disruption of specific chemokine receptor genes and ligand neutralizing reagents will be exploited to dissect specific chemokine network. Similar techniques, in conjunction with in vitro cell migration assays and the TNF-alpha neutralization model of murine reactivation tuberculosis, will be employed to evaluate the effects of TNF-alpha on the expression of specific chemokines and receptors, as well as on migration of T cells and monocytes during tuberculous infection. These studies should yield valuable information that will shed light on the roles of chemokines and receptors on cell migration, granuloma formation, and host defense in tuberculous infection.

描述(申请人提供)：肉芽肿在宿主防御结核分枝杆菌中起重要作用。然而，调节结核肉芽肿形成和维持的机制却知之甚少。趋化因子和趋化因子受体在生理和病理生理状态下的细胞迁移中起着重要的作用。新的证据表明，趋化因子和趋化因子受体在感染期间调节肉芽肿反应中发挥作用。结核分枝杆菌具有在体外和体内系统中调节趋化因子及其受体表达的能力。肿瘤坏死因子-α(TNF-α)对结核病的控制至关重要，是趋化因子表达和白细胞转运的有力调节因子。我们已经证明，中和持续性肺结核小鼠的肿瘤坏死因子-α会导致与肉芽肿组织紊乱和肺部弥漫性细胞浸润相关的疾病复发。基于这些观察，我们建议检验以下假设：i)趋化因子和趋化因子受体在结核病的细胞迁移和肉芽肿形成中起重要作用；ii)肿瘤坏死因子-α通过调节特定的趋化因子和趋化因子受体来调控感染部位的免疫细胞的运输，从而调节肉芽肿的反应。由于1型T细胞在抵抗结核分枝杆菌宿主防御中的重要性，将致力于检测能够调节这些T淋巴细胞迁移的趋化因子和受体的子集。小鼠结核病模型，以及免疫组织化学、激光显微解剖和实时聚合酶链式反应技术将被用来表征这些特定的趋化因子和受体在结核感染过程中的表达。特异性趋化因子受体基因和配体中和试剂被破坏的小鼠将被用来剖析特定的趋化因子网络。类似的技术，结合体外细胞迁移试验和小鼠再激活结核病的肿瘤坏死因子-α中和模型，将被用来评估肿瘤坏死因子-α对结核感染过程中特异性趋化因子和受体表达的影响，以及对T细胞和单核细胞迁移的影响。这些研究应该会产生有价值的信息，阐明趋化因子和受体在细胞迁移、肉芽肿形成和结核感染中的宿主防御中的作用。