Traffic from chronic mycobacterium induced granulomas

描述（由申请人提供）：结核病可以潜伏数十年，全世界有数十亿人感染，但这是人们对这种疾病知之甚少的阶段。在基因表达和蛋白质表达水平上，关于分枝杆菌病原体的休眠状态和病原体在宿主体内的适应性的研究数据激增。同时，对于潜伏期的宿主免疫反应，特别是局限于肉芽肿性炎性病变的免疫反应了解甚少。硬壁肉芽肿的作用是防止病原体的传播，也保护周围的宿主组织。它还在多大程度上保护细菌免受免疫系统的消毒，并可能阻止免疫系统进入病原体，这是未知的。目前迫切需要了解针对休眠分枝杆菌的特异性免疫反应的信息。特别是，很少甚至没有关于宿主树突状细胞（DC）能够在多大程度上取样由休眠的肉芽肿居住细菌专门表达的抗原的信息。同样，T细胞对潜伏期抗原的全身反应也没有被广泛表征。我们将用牛分枝杆菌卡介苗（BCG）感染模型诱导小鼠肝脏肉芽肿。含有肉芽肿的肝片将在慢性阶段移植到小鼠体内。利用荧光标记的DC， T细胞和细菌定位于慢性肉芽肿，我们将追踪他们的交通从移植。通过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呈递潜伏性分枝杆菌抗原的能力以及T细胞对潜伏性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，肉芽肿隔离的细菌是否能够诱导全身宿主免疫反应。这些实验的潜在答案可能对结核病疫苗的努力至关重要。这些实验将增加我们对其他感染性和自身免疫性肉芽肿疾病及其长期免疫病理的认识。

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.