Genes associated with Mycobacterium avium pathogenesis

描述(由申请人提供)：禽型分枝杆菌在免疫功能低下的患者和健康人中都会引起感染。感染主要发生在呼吸道，并呈播散性。细菌在宿主的不同环境中生存的能力需要严格的基因调控。在过去4年的资助中，我们揭示了禽类分枝杆菌与宿主相互作用的许多复杂方面，从细菌与宿主粘膜之间的相互作用，到在巨噬细胞中生存和传播的能力。鉴定了几个毒力基因，并对它们的功能进行了鉴定。许多基因允许细菌进入肠道上皮细胞，其他基因是在巨噬细胞内生存所必需的。这个项目的长期目标是了解病原体和宿主细胞之间的相互作用机制。我们的意见书现在包含了探索禽类分枝杆菌和巨噬细胞之间关系的拟议研究。我们的中心假设是，禽类分枝杆菌有特定的策略来颠覆宿主细胞，意识到这些策略将有助于改进预防和治疗禽类分枝杆菌相关疾病的手段。我们建议在下一个资助期间继续这项工作，评估：1.鸟分枝杆菌对巨噬细胞杀伤机制的干扰：(A)研究参与修改/干扰进入巨噬细胞的分枝杆菌空泡形成的细菌基因；(B)研究与细菌抵抗巨噬细胞杀伤机制相关的基因的作用机制；2.鸟分枝杆菌离开凋亡的巨噬细胞并扩散到周围巨噬细胞的机制。

DESCRIPTION (provided by applicant): Mycobacterium avium causes infection in both immunocompromised patients and in healthy individuals. The chiefly encountered infections are in the respiratory tract, and disseminated. The ability of the bacterium to survive in different environments in the host requires tight gene regulation. During the past 4 years of this grant, we have unveiled a number of the complex aspects of M. avium interaction with the host, from the interaction between the bacterium and the host mucosa, to the ability to survive in macrophages and to disseminate. Several virulence genes were identified and their functions characterized. Many of the genes allow the bacterium to enter intestinal epithelial cells, and others are required for survival within macrophages. The long-term goal of this project is to understand the mechanisms of interaction between the pathogen and host cells. Our submission now contains proposed studies to explore the relationship between M. avium and macrophages. Our central hypothesis is that M. avium has specific strategies to subvert the host cells and that becoming aware of them will allow for improved means of prevention and treatment of M. avium-related diseases. We propose to continue this work during the next funding period by evaluating: 1. M. avium interference with macrophage killing mechanisms: (a) studying bacterial genes that participate in modifying/interfering with the mycobacterial vacuole formation upon uptake into macrophages; (b) studying the mechanisms of action of genes associated with bacterial resistance to macrophage killing mechanisms; 2. The mechanisms by which M. avium leaves apoptotic macrophages and spreads to surrounding macrophages.