Intracellular Growth of Legionella Pneumophila

这项建议的长期目标是了解革兰氏阴性细菌病原体，嗜肺军团菌，如何能够在正常的杀菌吞噬细胞内存活和复制。该资助将侧重于确定嗜肺乳杆菌如何改变内吞途径并阻止宿主细胞的吞噬体-溶酶体融合。具体目的是通过检查两个关键的Dot蛋白，DotB和DotL，在Dot/Icm复合物的组装和活性中的作用来表征Dot装置，并确定该复合物输出到巨噬细胞宿主细胞的底物。这一提议与健康的关系是双重的。首先，建立嗜肺L在巨噬细胞内存活和复制的机制将为其如何引起疾病提供额外的见解，并可能揭示用于药物治疗的新靶点。其次，由于各种细菌病原体通常使用专门的分泌系统，因此对嗜肺乳杆菌分泌装置的了解可能适用于理解其他病原体使用的毒力分子机制，并可作为预防或治疗许多不同疾病的基础。

The long term objective of this proposal is to understand how a Gram negative bacterial pathogen, Legionella pneumophila, is able to survive and replicate inside normally bactericidal phagocytic cells. This grant will focus on determining how L. pneumophila alters the endocytic pathway and prevents phagosome-lysosome fusion of host cells. The specific aims are to characterize the Dot apparatus by examining the role of two critical Dot proteins, DotB and DotL, in the assembly and activity of the Dot/Icm complex and to identify the substrate(s) exported by this complex into the macrophage host cell. The health relatedness of this proposal is two fold. First, establishing the mechanism used by L, pneumophila to survive and replicate inside macrophages will provide additional insight into how it causes disease and may reveal novel targets to be used for drug therapy. Second, since specialized secretion systems are commonly used by a variety of bacterial pathogens, knowledge gained about the L. pneumophila secretion apparatus is likely to be applicable to understanding the molecular mechanisms of virulence used by other pathogens, and could serve as the basic to prevent or treat a number of different disease.