Salmonellosis continues to be a major world-wide health concern. Essential to the pathogenicity of Salmonella enterica is the function of a type III secretion system encoded within a pathogenicity island (SPI- 1) of its chromosome. This system mediates the delivery into the host cell of bacterial effector proteins which stimulate host cell responses including actin cytoskeleton rearrangements leading to bacterial uptake, production of pro-inflammatory cytokines, and the initiation of programmed cell death in macrophages. Previous work in our laboratory has focused on the characterization of the structural components of this secretion system, the identification of associated proteins that aid the secretion process, and the identification of secreted proteins that stimulate or interfere with cellular responses. We have also established that some of the components of the type III secretion apparatus are organized in a supramolecular structure, the needle complex, that spans the bacterial envelope and resembles the flagellar basal body. The proposed research project, a natural extension of the previous studies, is aimed at gaining a better understanding of the function of the centisome 63 type III secretion system of Salmonella enterica. More specifically we propose:!) To study the composition of the type III secretion-associated needle complex structure;2) To establish the assembly pathway of the type III secretion-associated needle complex;3) To investigate the function of InvC, the type III secretion-associated ATPase that is presumed to energize the secretion machinery;4) To identify the signals that allow the recognition of different secreted proteins by the secretion apparatus;and 5)/To investigate the regulatory function of SicA, a type III secretion-associated chaperone. These studies will enhance our understanding of the interaction of Salmonella with host cells. Since type HI secretions systejms are present in several important pathogenic bacteria, these studies may also help the development of novel antimicrobial drugs potentially effective against many bacterial pathogens.
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