Reactivation Tuberculosis in A/J Mice

描述(由申请人提供) 世界上四分之一的人口感染结核分枝杆菌 每年造成约290万人死亡。重新激活 结核病是当今成人结核病的主要原因，尽管 易于重新激活的机制是复杂和神秘的。自.以来 动物模型有助于了解结核病的发病机制，我们 进行了一系列研究，以标准化小鼠的急性、慢性 并通过改变小鼠品系、路线和剂量来重新激活结核病 感染。然后我们发现A/J小鼠高度易感，而C57BL/6 小鼠对进行性疾病的抵抗力相对较强 静脉注射。或通过气雾剂路线。A/J小鼠不能在肺部形成肉芽肿 巨噬细胞对结核分枝杆菌的杀伤作用存在缺陷。与C57BL/6小鼠不同，A/J小鼠 小鼠也经历了结核病的早期和几乎一致的重新激活。 遵循康奈尔大学的模式。A/J小鼠编码的基因有缺失 补体C5，在完整的小鼠中产生C5a过敏毒素，已知的 巨噬细胞细胞因子和趋化因子合成的调节因子。因此，在 在这次调查中，我们将检验C5a缺乏的假设 损害小鼠的免疫反应，允许重新激活 通过以下目标防治结核病。具体目标我会调查 C5基因缺失是否影响细胞因子的合成(肿瘤坏死因子α， IL-1-β和IL-6)，阻止巨噬细胞激活，从而阻止巨噬细胞 介导对A/J小鼠MTB的杀伤作用。SPICAL AIM 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A/J巨噬细胞并评估它们是否在引起 免疫细胞流入肺部，形成肉芽肿。特定的 目的III将表征组织学，细胞因子和趋化因子的反应 以确定A/J小鼠的免疫反应类型(Th1与Th2) 在结核病复活期间占主导地位。这些研究是 预计将加强我们对之前假定的机制的理解 结核病在小鼠肺部的重新激活最终帮助我们 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.