Cell Migration in Tuberculosis Infection

结核感染中的细胞迁移

• 批准号: 6899572
• 负责人: John R. Chan
• 金额: $ 5.01万
• 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/6899572
• 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（由申请人提供）：肉芽肿在宿主防御结核分枝杆菌方面发挥重要作用。然而，人们对调节结核性肉芽肿形成和维持的机制知之甚少。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发挥重要作用。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和趋化因子受体表达的能力。肿瘤坏死因子-α (TNF-α) 对于控制结核病至关重要，并且是趋化因子表达和白细胞运输的有效调节剂。我们已经证明，在患有持续性结核病的小鼠中中和 TNF-α 会导致与肺部肉芽肿瓦解和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协调结核病中的细胞迁移和肉芽肿形成中发挥重要作用； ii) TNF-α 通过调节特定趋化因子和趋化因子受体来指导感染部位免疫细胞的运输，从而调节肉芽肿反应。由于 1 型 T 细胞在宿主防御结核分枝杆菌中的重要性，我们将重点研究可调节这些 T 淋巴细胞迁移的趋化因子和受体子集。小鼠结核病模型以及免疫组织化学、激光显微切割和实时 PCR 技术将用于表征结核感染期间这些特定趋化因子和受体的表达。将利用破坏特定趋化因子受体基因和配体中和剂的小鼠来剖析特定趋化因子网络。类似的技术，结合体外细胞迁移测定和小鼠结核病再激活的TNF-α中和模型，将用于评估TNF-α对特定趋化因子和受体表达以及结核感染期间T细胞和单核细胞迁移的影响。这些研究应该产生有价值的信息，阐明趋化因子和受体在结核感染中细胞迁移、肉芽肿形成和宿主防御中的作用。