This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Shigella spp. are obligate intracellular pathogens and causative agents of shigellosis (a form of bacillary dysentery) that causes an estimated 1.1 million deaths per annum. The pathogenesis of Shigella involves the invasion of colonic epithelial cells. Once the bacteria have entered a cell they replicate and recruit actin filaments for directional movement within these cells and for subsequent invasion of adjacent cells. The Shigella outer membrane protein, IcsA is essential to Shigella pathogenesis in that this is the sole bacterial protein required for the recruitment of actin filaments. IcsA is expressed on a large 220-kilobase virulence plasmid found in all species of Shigella. Furthermore, IcsA is unique in that it is targeted and restricted to the old pole of the bacterium. Preliminary studies indicate that the asymmetrical distribution of IcsA is directly correlated with directional movement of Shigella within colonic epithelial cells and its efficient dissemination to uninfected cells. Therefore an understanding of the mechanisms by which IcsA is expressed, targeted to the old pole of the bacillus, secreted and maintained at the pole is important in addressing the pathogenic nature of Shigella. IcsA, an autotransported outer membrane protein is targeted to the old pole of the Shigella;the same pole where actin filaments are assembled for intracellular swimming and intercellular dissemination in host colonic epithelial cells. Several lines of evidence suggests that IcsA is targeted to the inner face of the cytoplasmic membrane before secretion and that IcsA must be targeted to the old pole before it is secreted. We have exploited these findings in a screen to identify a putative polar target for IcsA. We have also developed a screen to identify factors that are responsible for the expression and secretion of IcsA and to identify global regulators of IcsA and other virulence proteins in Shigella.
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