Traffic from chronic mycobacterium induced granulomas

来自慢性分枝杆菌诱导的肉芽肿的交通

• 批准号: 7471830
• 负责人: Matyas Sandor
• 金额: $ 18.17万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7471830
• 关键词: Address; Age; Animals; Antigens; Apoptosis; Autoimmune Process; Bacteria; Biology; CD4 Positive T Lymphocytes; Cells; Chimeric Proteins; Chronic; Clinical; Color; Data; Delayed Hypersensitivity; Dendritic Cells; Disease; DsRed; Environment; Epitopes; Explosion; Exposure to; Extracellular Matrix; Fibrosis; Fluorescence; Gene Expression; Genetic Transcription; Genus Mycobacterium; Granuloma; Granulomatous; Green Fluorescent Proteins; HIV Infections; Hepatic Granuloma; Homing; Human; ITGAX gene; Immune; Immune response; Immune system; Immunity; Immunocompetent; Immunosuppressive Agents; Immunotherapy; Individual; Infection; Inflammation; Inflammatory; Kidney; Label; Lesion; Liver; Localized; Measures; Microscopy; Modeling; Mouse Strains; Mus; Mycobacterium Infections; Mycobacterium bovis; Numbers; Organ; Pathology; Pharmaceutical Preparations; Population; Public Health; Reaction; Recombinants; Recruitment Activity; Research; Role; Sampling; Sentinel; Site; Specificity; Staging; Symptoms; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Thinking; Time; Tissues; Toxin; Transgenic Mice; Transgenic Organisms; Transplantation; Tuberculosis; Tuberculosis Vaccines; Vaccines; Week; capsule; design; diphtheria toxin receptor; immunopathology; interest; macrophage; mutant; mycobacterial; pathogen; prevent; promoter; protein expression; rBCG; research study; residence; response; trafficking; vaccine development

DESCRIPTION (provided by applicant): Tuberculosis can remain latent for decades, and billions of people worldwide are infected, yet this is the stage of the disease about which the least is known. There has been an explosion of research data about the state of dormancy of the mycobacterial pathogen and the adaption of the pathogen to residence in the host, both at the level of gene expression and protein expression. At the same time very little is known about host immune reactions during the period of latency, especially those reactions which are localized in the granulomatous inflammatory lesions. The hard walled granuloma acts to prevent the dissemination of the pathogen and also protects the surrounding host tissue. The extent to which it also shields the bacteria from sterilizing immunity and possibly prevents access of the immune system to the pathogen is unknown. There is an urgent need for information about the specific immune response against dormant mycobacteria. In particular, little to no information is available about the extent to which host dendritic cells (DC) are able to sample antigens exclusively expressed by dormant, granuloma dwelling bacteria. Similarly, the systemic response of T cells to latency antigens has not been widely characterized. We will induce granulomas in murine liver using a Mycobacterium bovis strain bacille Calmette Guirin (BCG) infection model. Liver pieces containing granulomas will be transplanted into mice at the chronic stage. By taking advantage of fluorescence-tagged DC, T cells and bacteria localized in chronic granulomas, we will trace their traffic from the transplant. By using combinations of genetically epitope-tagged BCG and T cell receptor transgenic mice we will also test the capacity of donor-derived DC to present latent mycobacterial antigens and the systemic response of T cells to latent mycobacterial antigens. PUBLIC HEALTH RELEVENCE:Our experiments will ask the key question of whether during chronic mycobacterial infection, the granuloma sequestered bacteria are able to induce a systemic host immune response or not. The potential answers from these experiments could be critically important to the tuberculosis vaccine effort. These experiments will increase our understanding of other infectious and autoimmune granulomatous diseases and their long- term immunopathologies.

描述（由申请人提供）：结核病可以保持潜在数十年，并且全球数十亿人被感染，但这是疾病的阶段。关于分枝杆菌病原体的休眠状态以及病原体对宿主中宿主的病原体的适应性的研究数据爆炸了，无论是基因表达和蛋白质表达水平。同时，关于潜伏期期间宿主免疫反应的了解很少，尤其是在肉芽肿性炎症病变中定位的那些反应。硬壁肉芽瘤可防止病原体的传播，并保护周围的宿主组织。它在多大程度上也屏蔽了细菌免疫免疫力，并可能阻止免疫系统进入病原体是未知的。迫切需要有关针对休眠分枝杆菌的特定免疫反应的信息。特别是，几乎没有关于宿主树突状细胞（DC）能够独家通过休眠，肉芽肿居住细菌的抗原的程度的信息。同样，T细胞对潜伏期抗原的全身反应尚未得到广泛的特征。我们将使用牛菌菌株Bacille Calmette Guirin（BCG）感染模型在鼠肝脏中诱导肉芽肿。在慢性阶段，含有肉芽肿的肝脏将被移植到小鼠中。通过利用荧光标记的直流，T细胞和慢性肉芽肿的细菌，我们将从移植物中追踪它们的流量。通过使用遗传表位标记的BCG和T细胞受体转基因小鼠的组合，我们还将测试供体衍生的DC呈现潜在的分枝杆菌抗原的能力，以及T细胞对潜在的分枝杆菌抗原的全身反应。公共卫生相关性：我们的实验将提出一个关键问题，即在慢性分枝杆菌感染期间，颗粒瘤隔离细菌是否能够诱导全身性宿主免疫反应。这些实验的潜在答案对于结核病疫苗工作至关重要。这些实验将增加我们对其他感染和自身免疫性肉芽肿性疾病及其长期免疫病理学的理解。