Traffic from chronic mycobacterium induced granulomas

描述(申请人提供)：结核病可以潜伏几十年，全世界有数十亿人被感染，但这是这种疾病最不为人所知的阶段。无论是在基因表达水平还是在蛋白质表达水平上，关于分枝杆菌病原菌的休眠状态和病原菌对寄主的适应能力的研究数据都呈爆炸式增长。同时，对潜伏期的宿主免疫反应，尤其是肉芽肿性炎性病变的免疫反应知之甚少。硬壁肉芽肿起到了防止病原体扩散的作用，同时也保护了周围的宿主组织。它还能在多大程度上保护细菌免受灭菌免疫，并可能阻止免疫系统接触病原体，目前尚不清楚。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)能够在多大程度上采样由休眠的肉芽肿寄生细菌独有表达的抗原的信息。同样，T细胞对潜伏抗原的系统反应也没有得到广泛的表征。我们将使用牛分枝杆菌卡介苗(BCG)感染模型诱导小鼠肝脏肉芽肿。含有肉芽肿的肝脏将在慢性期移植到小鼠体内。通过利用慢性肉芽肿中定位的荧光标记的DC、T细胞和细菌，我们将追踪它们从移植以来的交通。通过使用基因表位标记的卡介苗和T细胞受体转基因小鼠的组合，我们还将测试供体来源的DC呈递潜在分枝杆菌抗原的能力，以及T细胞对潜在分枝杆菌抗原的系统反应。公共卫生报道：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，肉芽肿隔离细菌是否能够诱导系统的宿主免疫反应。这些实验的潜在答案可能对结核病疫苗努力至关重要。这些实验将增加我们对其他传染性和自身免疫性肉芽肿疾病及其长期免疫病理机制的了解。

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.