Entry Mechanisms of Mycobacterium marinum

描述（由申请方提供）：海洋分枝杆菌是致病菌 代理的局部病变的四肢，通常称为游泳池或 水族馆肉芽肿。游泳池肉芽肿是比较常见的职业 几乎涉及任何水源，包括水族馆维护，捕鱼和 潜水目前，感染发生的频率为每年近200例， 仅在美国，而且被认为正在上升。改进的疾病治疗方法 预防是一个高度优先事项，因为抗生素治疗通常需要 多种药物和从四到十四个月前完全恢复。M. 在疾病期间，marinum主要在巨噬细胞中细胞内复制， 人类因此，M. marinum必须进入真核细胞才能复制， 参与进入的基因应该是产生疾病的关键。我们 以前的研究发现了两个关键方面， M的能力。marinum入侵宿主细胞。首先，我们发现M. marinum进入宿主细胞的水平高达100倍， 非致病性分枝杆菌M.恶臭这种进入机制似乎 提高M. marinum在细胞内存活。二是 M的能力。海产品进入宿主细胞受生长条件的调节。我们 利用这些数据开发了分离基因的新策略 需要输入M。marinum进入宿主细胞。近基因 M的关系。marinum与其他分枝杆菌物种如M. Avium和 尤其是M。结核病，表明所确定的基因可能发挥作用， 在其他致病性分枝杆菌中具有类似作用。我们的假设是 进入宿主细胞的能力对于分枝杆菌的毒力是重要的。的 本提案的具体目标是：1）分离和表征 参与进入的分枝杆菌基因和2）决定这些基因的参与 基因在小鼠体内的毒性。通过对进入机制的审查， 以及调节它的因素，我们希望进一步了解 分枝杆菌引起疾病以及提供洞察新的方法， 他们的预防。

DESCRIPTION (provided by the applicant): Mycobacterium marinum is the causative agent of localized lesions in the extremities, commonly called swimming pool or aquarium granuloma. Swimming pool granuloma is relatively common in professions involving almost any water source, including aquarium maintenance, fishing and diving. Currently, infections occur at a frequency of nearly 200 per year in the U.S. alone and are thought to be on the rise. Improved methods for disease prevention are a high priority, since antibiotic therapy usually requires multiple drugs and from four to fourteen months before full recovery. M. marinum replicates primarily intracellularly in macrophages during disease in humans. Thus, M. marinum must enter a eukaryotic cell in order to replicate and the genes involved in entry should be critical for production of disease. Our previous studies have resulted in the discovery of two key aspects of the ability of M. marinum to invade host cells. First, we have found that M. marinum enters host cells at up to 100 fold higher levels than the non-pathogenic mycobacterial strain M. smegmatis. This entry mechanism appears to enhance the ability of M. marinum to survive intracellularly. Second, the ability of M. marinum to enter host cells is regulated by growth conditions. We have utilized these data to develop novel strategies for isolation of the genes required for entry of M. marinum into host cells. The close genetic relationship of M. marinum to other mycobacterial species such as M. avium and particularly M. tuberculosis, suggests that the genes identified may play a similar role in other pathogenic mycobacteria. Our hypothesis is that the ability to enter host cells is important for virulence of mycobacteria. The specific aims of the current proposal are: 1) isolate and characterize mycobacterial genes involved in entry and 2) determine the involvement of these genes in virulence in mice. Through an examination of the mechanisms of entry and the factors that regulate it, we hope to further our understanding of how mycobacteria cause disease as well as provide insight into novel methods for their prevention.