A Comparative Study of M. tuberculosis and M. bovis BCG of T cell responses

描述(申请人提供)：结核分枝杆菌通常被称为“最成功的”人类病原体，因为当一个人被细菌感染时，很少从他们的系统中清除感染的有机体。结核分枝杆菌可以在人类中持续存在，但后来在免疫受损的情况下重新激活，这些情况破坏了宿主免疫系统的平衡，因为它与感染微生物相互作用，例如与艾滋病毒合并感染或使用抗炎药物治疗类风湿性关节炎。因此，理解结核病最重要的问题之一是细菌具有非常有效的机制来逃避获得性免疫消除。为了控制结核分枝杆菌的感染，宿主免疫系统必须产生适应性免疫反应，如果没有这种反应，患者就会死于压倒性的结核杆菌感染。效应器CD4T细胞对控制结核感染特别重要，然而，它们不足以清除宿主中的细菌。结核分枝杆菌逃避或干扰T细胞在宿主中的激活和识别，可以解释这种病原体在宿主中的持久性，这使得进一步研究T细胞对分枝杆菌的反应具有特别重要的意义。在结核分枝杆菌和卡介苗(分枝杆菌的减毒株)感染的动物模型中，两者都表现出相似的获得性免疫激活动力学；然而，与结核分枝杆菌相反，对牛卡介苗的免疫反应导致细菌从宿主中被消灭。我们假设，这两种分枝杆菌之间感染的二分结果是效应性T细胞不同激活的结果。我们将使用共聚焦和双光子显微镜技术来评估和比较肺中分枝杆菌感染细胞抗原特异性CD4T细胞识别的频率和质量。通过确定T细胞与结核分枝杆菌和卡介苗感染细胞相互作用的频率和质量的差异，我们将进一步了解结核分枝杆菌感染期间T细胞指令的崩溃，并允许病原体逃避效应器T细胞识别并在宿主内持续存在。

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis is frequently called "the most successful" human pathogen, owing to the fact that when an individual has been infected by the bacteria, one very rarely eliminates the infecting organism from their system. M. tuberculosis can persist in humans only to become reactivated later under immune compromised situations that disrupt the equilibrium of the host immune system as it interacts with the infecting microbe, such as co-infection with HIV or treatment with anti-inflammatory drugs for rheumatoid arthritis. Therefore, one of the most important problems in understanding TB is that the bacteria possess very effective mechanisms of evading elimination by adaptive immunity. In order to control an infection with M. tuberculosis the host immune system must generate an adaptive immune response, and without such a response, patients succumb to an overwhelming M. tuberculosis infection. Effector CD4 T cells are especially important for the control of a TB infection, however, they are not sufficient to eliminate bacteria from the host. M. tuberculosis evading or disrupting T cell activation and recognition in the host, could explain the persistence of this pathogen within its host; this makes further studies of T cell responses to Mycobacterium of particular importance. In animal models of infection with M. tuberculosis and M. bovis BCG (an attenuated strain of mycobacterium), both show similar kinetics of adaptive immune activation; however, in contrast to M. tuberculosis, the immune response to M. bovis BCG results in the eradication of the bacteria from its host. We hypothesize that the dichotomous outcome of infection between these two strains of mycobacterium are the result of a differential activation of effector T cells. We will use the techniques of confocal and two-photon microscopy to assess and compare the frequency and quality of antigen-specific CD4 T cell recognition of mycobacterium infected cells in the lung. By identifying differences in the frequency and the quality of T cell interactions with M. tuberculosis and M. bovis BCG infected cells, we will further understand the breakdown in T cell instruction that occurs during M. tuberculosis infection and allows the pathogen to evade effector T cell recognition and persist within its host.