Reactivation Tuberculosis in A/J

描述（由申请人提供） 世界上有四分之一的人口感染了M。结核 导致每年约290万人死亡。再活化 结核病是当今成人结核病的主要原因， 导致再激活的机制是复杂和神秘的。以来 动物模型对于了解结核病的发病机制是有用的，我们 进行了一系列研究，以标准化急性，慢性 以及通过改变小鼠品系、途径和剂量， 感染我们发现A/J小鼠高度易感，而C57 B1/6小鼠高度易感， 当小鼠被感染时， 静脉注射或通过气雾剂途径。A/J小鼠不能在肺中形成肉芽肿 并且它们的巨噬细胞在杀死MTB方面有缺陷。与C57 B1/6小鼠不同，A/J 小鼠也经历了早期和几乎一致的结核病复发 遵循康奈尔模式。A/J小鼠在编码以下的基因中具有缺失： 补体C5，在完整的小鼠中产生C5 a过敏毒素， 巨噬细胞的细胞因子和趋化因子合成的调节剂。因此在 在这项研究中，我们将检验缺乏C5 a的假设， 损害了小鼠的免疫反应， 结核病的治疗方法有以下几种。具体目标我会调查 C5基因的缺失是否影响细胞因子（TNF α， IL-1-β和IL-6），防止巨噬细胞活化，从而防止巨噬细胞 介导的A/J小鼠中MTB的杀伤。具体目标II将调查 C5基因缺失对结核分枝杆菌分泌趋化因子的影响 感染的A/J巨噬细胞，并评估它们是否在引起 免疫细胞流入肺部并形成肉芽肿。 具体 目的III将描述组织学，细胞因子和趋化因子的反应， 在A/J小鼠的肺中测定免疫应答的类型（Th 1对Th 2）， 在结核病的复发过程中占主导地位。这些研究 预计将加强我们对假定机制的理解， 肺结核在小鼠肺中的重新激活，并最终帮助我们 制定更好的策略来预防人类结核病。

DESCRIPTION (provided by applicant) One quarter of the world's population is infected with M. tuberculosis resulting in approximately 2.9 million deaths each year. Reactivation tuberculosis is the major cause of adult tuberculosis today although the mechanisms that predispose to reactivation are complex and enigmatic. Since animal models are useful for understanding pathogenesis of tuberculosis, we performed a series of studies to standardize murine models of acute, chronic and reactivation tuberculosis by varying the mouse strain, route and dose of infection. We then found that A/J mice were highly susceptible while C57Bl/6 mice were relatively resistant to progressive disease when infected either i.v. or via aerosol routes. A/J mice were unable to form granulomas in lungs and their macrophages were defective in killing MTB. Unlike C57Bl/6 mice, A/J mice also underwent an early and near uniform reactivation of tuberculosis following the Cornell model. A/J mice have a deletion in the gene encoding for Complement C5 which in intact mice yields the C5a anaphylatoxin, a known regulator of cytokine and chemokine synthesis of macrophages. Therefore, in this investigation, we will examine the hypothesis that the lack of C5a compromises the immune responses in mice allowing the reactivation of tuberculosis through the following aims. Specific Aim I will investigate whether the deletion in C5 gene affects the synthesis of cytokines (TNF alpha, IL1-beta and IL-6), prevents macrophage activation and thereby macrophage mediated killing of MTB in A/J mice. Specific Aim II will investigate the effects of the deletion in C5 gene to the secretion of chemokines by MTB infected A/J macrophages and evaluate whether they are important in causing influx of immune cells into the lungs and formation of granulomas. Specific Aim III will characterize histological, cytokine and chemokine responses of lungs in A/J mice to determine the type of immune response (Th1 vs Th2) that dominates during the reactivation of tuberculosis. These studies are anticipated to enhance our understanding on putative mechanisms that precede the reactivation of tuberculosis in the lungs of mice and ultimately help us to develop better strategies to prevent tuberculosis in man.