Microbial pathogenicity is largely determined by virulence factors that interface with host cells and tissues to promote colonization and survival. The goal of this proposal is to develop a better understanding of the mechanisms through which virulence factors expressed by enteropathogenic Yersiniae utilize host cell factors to promote disease. One of the major virulence factors produced by these bacteria is invasin, which plays a crucial role in pathogenicity by binding to beta-1 integrins present on the surface of host cells and facilitating invasion of the intestinal epithelium. This proposal tests the hypothesis that specific integrin dependent signaling networks in the host are targeted by the Yersiniae to promote invasion. Whereas these pathways are activated during the initial invasion process, however, they are effectively subverted at later stages in infection by the activities of other virulence factors, thus allowing for extracellular growth of the pathogen. A second facet of this hypothesis is that components of integrin-dependent signaling networks eventually overcome the inhibitory actions of these virulence factors and facilitate clearance of the bacteria from the intestine. The following specific aims have been developed to address these hypotheses:
Aim 1 : Using in vitro cell culture models, we propose to investigate the molecular organization and regulation of integrin-dependent signaling networks established in macrophages during the course ofYersinia uptake.
Aim 2 : One component of integrin-dependent signaling pathways that has been strongly implicated in aspects of Yersinia pathogenicity is the Src family kinases.
This aim will explore the function of these proteins in the course of Yersinia infection with the use of Src family knockout mice.
Aim 3 : These mouse models will also be used, together with a panel of Yersinia strains that contain mutations in specific cellular adhesins, to explore the functional relationship between Yersinia virulence factors and Src family kinases during the course of bacterial invasion and colonization. Completion of these studies will help to generate a comprehensive understanding of the host cell and microbial mechanisms involved in Yersinia pathogenicity and, in the process, provide insight into other integrin-dependent pathways.
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