CHRONIC TUBERCULOSIS--LATENT OR DYNAMIC

慢性结核病——潜伏性或动态性

• 批准号: 6124215
• 负责人: IAN M ORME
• 金额: $ 22.35万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-10 至 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6124215
• 关键词: antigen presentation; bacteria characteristic; bacterial antigens; bactericidal immunity; cell population study; chemokine; chronic disease /disorder; cytokine; granuloma; guinea pigs; histology; immunocytochemistry; laboratory mouse; latent bacterial disease; pathologic process; phenotype; tuberculosis

DESCRIPTION (Adapted from the Applicant's Abstract): It is estimated that about one third of the world's population has been exposed to tuberculosis. It is not known how many of these individuals harbor live bacilli in a form of latent tuberculosis, but it may be a significant percentage. Exactly why tuberculosis takes a chronic/latent form in many people is not understood, nor is it clear what conditions [other than immune deficiency] can cause the disease to reactivate from latent to active infection. The purpose of this proposal is to use mouse and guinea pig animal models to attempt to understand these events more clearly. Following aerosol exposure to low doses of Mycobacterium tuberculosis both animal species initially develop a chronic disease state in which the bacterial load remains essentially constant. In some strains of mice this state persists for the lifespan of the animal, during which several definable stages were seen in which cell populations increased and then declined within the granuloma, and were replaced by an increasingly fibrotic response. Moreover, in certain susceptible inbred mouse strains and in guinea pigs the disease reactivates after a period of time. Together, these data seem to imply that the granulomatous response in the lungs is a continuing dynamic event, and is probably driven not by truly latent bacteria, but by bacteria trying periodically to reactivate. Accordingly, we propose to study these events over the course of the disease using a battery of histology, immuno-histochemistry, and immunological techniques. We will study the kinetics of influx and apparent loss of cell populations in the lung granuloma, the expression of cytokine, chemokine, and blood vessel adhesion molecules, and the phenotype, cytokine profile, and antigen recognition of incoming T cells. As a result, we should be able to formulate a picture of how the granuloma is built, and why it gradually degenerates. In addition we will test our working hypothesis that mice that rely more heavily on innate rather than acquired immunity in the lungs are much more prone to reactivation disease, as well as a hypothesis regarding the detection of these events in the guinea pig model by skin testing. Finally, a third component of this grant application will look at the infecting bacilli directly, by studying potential changes in bacterial structure induced in adaptation to changes now understood to exist in the phagosomal environment. In this latter endeavor we shall be assisted by highly qualified mycobacterial chemists from within the Mycobacteria Research Laboratories [MRL] at CSU.

描述（改编自申请人的摘要）：估计 世界上大约三分之一的人口已经接触过 结核。目前尚不清楚这些人中有多少人还活着 杆菌以潜伏性结核病的形式存在，但它可能是一个重要的 百分比。到底为什么结核病在许多地方呈慢性/潜伏形式 人们不理解，也不清楚什么条件[除了 免疫缺陷]可导致疾病从潜伏期重新激活 活动性感染。该提案的目的是使用鼠标和 豚鼠动物模型试图更多地了解这些事件 清楚地。气溶胶暴露于低剂量分枝杆菌后 结核病 这两种动物最初都会发展为一种慢性疾病 细菌负荷基本保持恒定的状态。在一些 在小鼠品系中，这种状态在动物的一生中持续存在， 在此期间，可以看到几个可定义的阶段，其中细胞 肉芽肿内的数量先增加后减少，并且 取而代之的是日益纤维化的反应。此外，在某些 易感近交系小鼠和豚鼠中存在该疾病 一段时间后重新激活。这些数据加起来似乎意味着 肺部的肉芽肿反应是一种持续的动态 事件，并且可能不是由真正的潜伏细菌驱动的，而是由 细菌尝试定期重新激活。据此，我们建议 使用一组数据来研究疾病过程中的这些事件 组织学、免疫组织化学和免疫学技术。我们将 研究细胞群流入和明显损失的动力学 肺肉芽肿、细胞因子、趋化因子和血液的表达 血管粘附分子、表型、细胞因子谱和 传入 T 细胞的抗原识别。结果，我们应该能够 描绘肉芽肿的形成方式及其原因 逐渐退化。此外，我们将测试我们的工作假设 那些更依赖先天免疫而不是后天免疫的小鼠 肺部更容易发生再激活疾病，以及 关于在豚鼠中检测到这些事件的假设 模型通过皮肤测试。最后，这笔赠款的第三个组成部分 应用程序将通过研究直接查看感染杆菌 适应环境引起的细菌结构的潜在变化 现在认为变化存在于吞噬体环境中。在这个 后者的努力将得到高素质分枝杆菌的协助 来自分枝杆菌研究实验室 [MRL] 的化学家 科罗拉多州立大学。