Cell Migration in Tuberculosis Infection

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，与人类共存了数千年。尽管只有约10%的感染个体发展为活动性结核病，但潜伏感染者的剪切数量导致每年全世界800万新的TB病例和200万死亡。免疫反应的M。结核病进展缓慢，但最终形成肉芽肿。这种免疫细胞的集合不仅起到将免疫应答集中在受感染的巨噬细胞区域的作用，而且还起到免疫屏障的作用，以防止感染在整个肺部传播。有趣的是，M.结核杆菌可以在肉芽肿中存活并持续存在，并且这种结构似乎通过在肺部引起病理而极大地促进疾病的传播。因此，肉芽肿是宿主和病原体的中间目标。这使得识别对M的免疫应答的“保护性”和“病理性”特征成为可能。结核病复杂而棘手。作为过去14年的合作项目，我们研究了导致结核病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剂。接受TNF中和剂治疗的人患结核病的风险显著增加。我们建议跟进我们以前的研究结果，在结核病小鼠模型中研究TNF和细胞迁移的方面。具体来说，我们将确定机制的促炎和抗炎机制相关的TNF在M。结核感染（Aim 1），产生新的诱导型敲除菌株以确定哪种细胞类型负责控制感染的各个阶段（Aim 2），并追踪令人惊讶的发现，即趋化因子受体CXCR 3可能损害宿主控制M.结核感染（目标3）。我们的目标是更好地了解感染过程中宿主和病原体之间的相互作用，以确定消除持久性有机体的策略。

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.