Cell Migration in Tuberculosis Infection

描述（申请人提供）：肉芽肿在宿主防御M.结核然而，调节结核性肉芽肿形成和维持的机制知之甚少。趋化因子及其受体在生理和病理状态下的细胞迁移中起重要作用。新出现的证据表明趋化因子和趋化因子受体在感染过程中调节肉芽肿反应中的作用。M.结核病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）是控制结核病所必需的，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会导致与肉芽肿组织解体和肺中弥漫性细胞浸润相关的疾病复发。基于这些观察结果，我们提出测试以下假设：i）趋化因子和趋化因子受体在结核病中协调细胞迁移和肉芽肿形成中起重要作用;和ii）TNF-α通过调节特异性趋化因子和趋化因子受体在感染部位指导免疫细胞的运输来调节肉芽肿反应。由于1型T细胞在宿主防御M.结核病，努力将集中在检查一个子集的趋化因子和受体，可以调节这些T淋巴细胞的迁移。鼠结核病模型，以及免疫组织化学，激光显微切割，和实时PCR技术将被用来表征这些特定的趋化因子和受体在结核感染的表达。将利用具有特异性趋化因子受体基因和配体中和试剂的破坏的小鼠来剖析特异性趋化因子网络。将采用类似的技术，结合体外细胞迁移试验和小鼠再活化结核病的TNF-α中和模型，评价TNF-α对特异性趋化因子和受体表达的影响，以及对结核病感染期间T细胞和单核细胞迁移的影响。这些研究将产生有价值的信息，将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。

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.