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

结核分枝杆菌和牛分枝杆菌卡介苗T细胞反应的比较研究

• 批准号: 8434279
• 负责人: Patricia Grace
• 金额: $ 4.22万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8434279
• 关键词: Address; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antigen Presentation; Antigen-Presenting Cells; Antigens; Attenuated; Bacteria; Behavior; Biology; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Communication; Cells; Characteristics; Clinical; Comparative Study; Cultured Cells; Data; Dendritic Cells; Development; Disease; Equilibrium; Frequencies; Genus Mycobacterium; Goals; HIV; Histocompatibility Antigens Class II; Human; Image; Immune; Immune response; Immune system; Immunity; Immunocompetent; Immunology; In Vitro; Individual; Infection; Infection Control; Inferior; Instruction; Kinetics; Laboratories; Life; Lung; Methods; Microbe; Microscopy; Mus; Mycobacterium tuberculosis; Organism; Outcome; Patients; Pharmaceutical Preparations; Process; Public Health; Publications; Reagent; Recording of previous events; Reporting; Research; Rheumatoid Arthritis; Site; Sterility; Structure of parenchyma of lung; System; T cell response; T-Cell Activation; T-Lymphocyte; Techniques; Testing; Time; Training; Tuberculosis; Tuberculosis Vaccines; Update; Virulent; Work; adaptive immunity; biomedical scientist; career; design; immune activation; in vivo; indexing; innovation; macrophage; novel vaccines; pathogen; public health relevance; public health research; research study; residence; response; tuberculosis immunity; two-photon; vaccine development

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.

描述（由申请人提供）：结核分枝杆菌通常被称为“最成功的”人类病原体，这是因为当一个人被细菌感染时，很少会从其系统中消除感染生物体。结核分枝杆菌可以在人类中持续存在，只能在免疫受损的情况下重新激活，因为它与感染微生物相互作用时，会破坏宿主免疫系统的平衡，例如与HIV的感染或用抗炎药治疗类风湿性关节炎。因此，理解结核病的最重要问题之一是，细菌具有通过自适应免疫消除消除的非常有效的机制。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的免疫反应，并且如果没有这种反应，患者屈服于结核分枝杆菌感染。效应子CD4 T细胞对于控制结核病感染尤其重要，但是，它们不足以从宿主中消除细菌。探测或破坏宿主中T细胞激活和识别的结核分枝杆菌可以解释该病原体在其宿主中的持久性。这进一步研究了T细胞对分枝杆菌特别重要的反应。在结核分枝杆菌和牛菌BCG（分枝杆菌菌株）感染的动物模型中，两者都显示出适应性免疫激活的类似动力学。然而，与结核分枝杆菌相比，对牛乳杆菌BCG的免疫反应导致从其宿主中消除细菌。我们假设这两种分枝杆菌之间感染的二分法结果是效应T细胞的差异激活的结果。我们将使用共聚焦和两光子显微镜的技术来评估和比较肺部受感染细胞的抗原特异性CD4 T细胞识别的频率和质量。通过鉴定T细胞与结核分枝杆菌和BCG M. bcg感染细胞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发生的T细胞指导的分解，并允许病原体逃避效应T细胞识别并在其宿主中持久。