Structural Genomics of the Yersinia Yop Virulon

鼠疫耶尔森氏菌，鼠疫的病原体，可以说是历史上最致命的病原体，在现代至少造成了2亿人死亡。该项目的主要目标是确定鼠疫杆菌效应蛋白的三维结构，这是毒力因子（耶尔森氏菌外蛋白或Yops）的一个子集，它被注射到哺乳动物细胞的细胞质中，使病原体能够逃避受感染生物体的免疫反应。我们还对某些效应物分泌所需的特异性Yop伴侣蛋白（Syc）感兴趣。我们的长期目标是促进设计或发现有效的对策，以对付这种潜在的生物恐怖主义。此外，由于许多重要的动物病原体采用类似的毒力策略（例如，志贺氏菌、肠致病性大肠杆菌、沙门氏菌、铜绿假单胞菌、鹦鹉热衣原体和博德特拉氏菌），我们预计其中一些蛋白质将成为一般“抗致病性”药物的合适靶点。与此同时，我们也在努力确定哺乳动物细胞中鼠疫杆菌效应物的目标，以便我们开始了解这种臭名昭著的细菌是如何解除免疫系统的武装并在宿主的淋巴组织中繁殖的。

Yersinia pestis, the causative agent of plague, is arguably the deadliest pathogen in history, having been credited with at least two-hundred million deaths in modern times. The principal objective of this project is to determine the three-dimensional structures of the Y. pestis effector proteins, a subset of the virulence factors (Yersinia outer proteins, or Yops) that are injected into the cytosol of mammalian cells and enable the pathogen to evade the immune response of the infected organism. We are also interested in specific Yop chaperone (Syc) proteins that are required for the secretion of some effectors. Our long-term goal is to facilitate the design or discovery of effective countermeasures for this potential agent of bioterrorism. In addition, since many important animal pathogens employ a similar virulence strategy (e.g., Shigella spp., enteropathogenic E. coli, Salmonella spp., Pseudomonas aeruginosa, Chlamydia psittaci, and Bordetella spp.), we expect that some of these proteins will be appropriate targets for general "antipathogenicity" drugs. At the same time, we are also trying to identify the targets of Y. pestis effectors in mammalian cells so that we may begin to understand how this infamous bacterium disarms the immune system and multiplies in the lymphoid tissues of its host.