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: 8232541
• 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 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8232541
• 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. 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.

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，因为当一个人被细菌感染时，一个人很少从他们的系统中消除感染生物体。结核分枝杆菌可以在人体内持续存在，只有在免疫受损的情况下才会重新激活，这种情况会破坏宿主免疫系统的平衡，因为它与感染微生物相互作用，例如合并感染艾滋病毒或使用抗炎药物治疗类风湿性关节炎。因此，了解结核病最重要的问题之一是细菌具有非常有效的逃避适应性免疫消除的机制。为了控制结核分枝杆菌感染，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分枝杆菌感染。效应CD4 T细胞对于控制结核感染尤其重要，然而，它们不足以消除宿主的细菌。结核分枝杆菌逃避或破坏宿主内T细胞的激活和识别，可以解释这种病原体在其宿主内的持久性；这使得进一步研究T细胞对分枝杆菌的反应变得尤为重要。在感染结核分枝杆菌和牛分枝杆菌卡介苗（一种分枝杆菌的减毒株）的动物模型中，两者都显示出相似的适应性免疫激活动力学；然而，与结核分枝杆菌不同的是，对牛分枝杆菌的免疫反应导致从宿主中消灭细菌。我们假设这两株分枝杆菌感染的两种结果是效应T细胞的不同激活的结果。我们将使用共聚焦和双光子显微镜技术来评估和比较肺分枝杆菌感染细胞抗原特异性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牛分枝杆菌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细胞指令的中断，从而使病原体逃避效应T细胞的识别并在其宿主内持续存在。