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

描述（由申请人提供）：结核分枝杆菌经常被称为“最成功的”人类病原体，这是因为当个体被细菌感染时，很少有人能从其系统中消除感染微生物。M.结核病可以在人体内持续存在，只是在免疫受损的情况下被重新激活，这种情况在与感染微生物相互作用时破坏宿主免疫系统的平衡，例如与HIV共感染或用抗炎药物治疗类风湿性关节炎。因此，了解结核病的最重要的问题之一是，细菌具有非常有效的机制，通过适应性免疫逃避消除。为了控制M.结核病时，宿主免疫系统必须产生适应性免疫应答，如果没有这种应答，患者就会屈服于压倒性的M。肺结核感染。效应CD 4 T细胞对于控制TB感染特别重要，然而，它们不足以从宿主中消除细菌。M.结核分枝杆菌逃避或破坏宿主中T细胞的活化和识别，可以解释这种病原体在其宿主中的持久性;这使得进一步研究T细胞对分枝杆菌的应答特别重要。在感染M.结核和M.牛BCG（分枝杆菌的减毒株），两者显示出相似的适应性免疫激活动力学;结核病，对M.牛BCG导致细菌从其宿主中根除。我们假设这两种分枝杆菌菌株之间感染的二分结果是效应T细胞的差异活化的结果。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的抗原特异性CD 4 T细胞识别的频率和质量。通过识别T细胞与M.结核和M.牛BCG感染的细胞，我们将进一步了解在M.结核感染，并允许病原体逃避效应T细胞识别，并在其宿主内持续存在。 公共卫生相关性：T细胞对M.结核病是研制预防结核病疫苗的关键一步。我们的目标是了解T细胞与M相互作用的动力学。肺组织内结核感染的细胞，以阐明病原体逃避根除的机制。对这些关键机制的理解将有助于设计新的疫苗，更有效地靶向和激活效应T细胞，以保护人类免受结核病的侵害。

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. PUBLIC HEALTH RELEVANCE: The study of T cell responses to M. tuberculosis represents a critical step towards the development of vaccines to protect against tuberculosis. We aim to understand the dynamics of T cell interactions with M. tuberculosis infected cells within lung tissue to elucidate mechanisms employed by the pathogen to evade eradication. An understanding of these key mechanisms will assist in the efforts to design novel vaccines that more efficiently target and activate effector T cells to protect humans from tuberculosis.