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: 8129135
• 负责人: Patricia Grace
• 金额: $ 4.18万
• 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/8129135
• 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 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，因为当一个人被该细菌感染时，人们很少能从其系统中消除感染生物体。结核分枝杆菌可以在人类体内持续存在，但随后会在免疫受损的情况下重新激活，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，了解结核病最重要的问题之一是细菌拥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，但它们不足以消除宿主中的细菌。结核分枝杆菌逃避或破坏宿主体内 T 细胞的激活和识别，可以解释这种病原体在宿主体内的持续存在；这使得进一步研究 T 细胞对分枝杆菌的反应显得尤为重要。在结核分枝杆菌和牛分枝杆菌 BCG（分枝杆菌减毒株）感染的动物模型中，两者均表现出相似的适应性免疫激活动力学。然而，与结核分枝杆菌相反，对牛分枝杆菌 BCG 的免疫反应会导致细菌从宿主中根除。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 细胞差异激活的结果。我们将使用共焦和双光子显微镜技术来评估和比较肺部分枝杆菌感染细胞的抗原特异性 CD4 T 细胞识别的频率和质量。通过识别 T 细胞与结核分枝杆菌和牛分枝杆菌 BCG 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发生的 T 细胞指令的崩溃，并使病原体能够逃避效应 T 细胞识别并在其宿主体内持续存在。 公共卫生相关性：T 细胞对结核分枝杆菌反应的研究代表了开发预防结核病疫苗的关键一步。我们的目标是了解 T 细胞与肺组织内结核分枝杆菌感染细胞相互作用的动态，以阐明病原体逃避根除的机制。了解这些关键机制将有助于设计更有效地靶向和激活效应 T 细胞的新型疫苗，以保护人类免受结核病的侵害。