Entry Mechanisms of Mycobacterium marinum

描述(申请人提供)：致病原因为海洋分枝杆菌 四肢局部病变的药剂，通常称为游泳池或 水族性肉芽肿。泳池肉芽肿在职业中相对常见 几乎涉及任何水源，包括水族馆维护、捕鱼和 潜水。目前，感染的频率为每年近200例。 只有美国，而且被认为正在崛起。改进的疾病治疗方法 预防是重中之重，因为抗生素治疗通常需要 服用多种药物，在完全康复前需要4到14个月的时间。M. 在疾病期间，海参主要在巨噬细胞内复制 人类。因此，海洋分枝杆菌必须进入真核细胞才能复制和 参与进入的基因应该对疾病的产生起关键作用。我们的 以前的研究发现了两个关键的方面 海洋分枝杆菌入侵宿主细胞的能力。首先，我们发现M。 海洋进入宿主细胞的水平比 非致病分支杆菌污垢分枝杆菌。此时将出现此进入机制 提高海洋微囊藻在细胞内存活的能力。第二， 海洋分枝杆菌进入宿主细胞的能力受生长条件的调节。我们 利用这些数据开发了分离基因的新策略 这是海洋分枝杆菌进入宿主细胞所必需的。亲近的基因 海洋分枝杆菌与其他分枝杆菌种的关系 尤其是结核分枝杆菌，表明所识别的基因可能在 在其他致病分枝杆菌中的作用类似。我们的假设是 进入宿主细胞的能力对分枝杆菌的毒力很重要。这个 当前提案的具体目标是：1)分离和表征 分枝杆菌基因参与进入和2)决定参与这些 小鼠的毒力基因。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它是如何 分枝杆菌导致疾病，并提供了对治疗的新方法的洞察 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.