CHRONIC TUBERCULOSIS--LATENT OR DYNAMIC

慢性结核病——潜伏性或动态性

• 批准号: 6294685
• 负责人: IAN M ORME
• 金额: $ 2.2万
• 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/6294685
• 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 世界上三分之一的人口都接触过 结核目前尚不清楚这些个体中有多少人生活在 结核杆菌的潜伏形式，但它可能是一个重要的 百分比。为什么结核病在许多人中以慢性/潜伏形式存在？ 人们不理解，也不清楚什么条件[除了 免疫缺陷]可以导致疾病从潜伏期重新激活， 活动性感染这个建议的目的是使用鼠标和 豚鼠动物模型，试图了解这些事件更多 清楚在暴露于低剂量的分枝杆菌的气溶胶之后， 结核病这两种动物最初都发展为慢性疾病 细菌负荷基本保持恒定的状态。在一些 小鼠品系的这种状态在动物的一生中持续存在， 在此期间，在哪个细胞中可以看到几个可定义的阶段， 在肉芽肿内，细胞数量增加，然后下降， 取而代之的是越来越严重的纤维化反应此外，在某些 易感的近交系小鼠品系和豚鼠的疾病 在一段时间后重新激活。综合来看，这些数据似乎表明 肺部的肉芽肿反应是一个持续的动态过程 事件，可能不是由真正的潜伏细菌驱动，而是由 细菌周期性地试图重新激活。因此，我们建议 研究这些事件在疾病的过程中使用电池， 组织学、免疫组织化学和免疫学技术。我们将 研究细胞群体的流入和表观损失的动力学， 肺肉芽肿，细胞因子，趋化因子，血 血管粘附分子，表型，细胞因子谱， 进入的T细胞的抗原识别。因此，我们应该能够 来阐明肉芽肿是如何形成的， 逐渐退化。此外，我们将测试我们的工作假设 更依赖先天免疫而非后天免疫的小鼠 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 皮肤测试模型最后，该补助金的第三部分 应用程序将直接查看感染杆菌，通过研究 细菌结构的潜在变化， 现在已经知道存在于吞噬体环境中的变化。在这 在后一项奋进中，我们将由高质量的分枝杆菌 来自分枝杆菌研究实验室[MRL]的化学家， 鉴证组