Relevance of the proposed research to public health: Salmonella serotypes are the leading cause of food- borne infections with lethal outcome in the United States. The increasing prevalence of S. typhimurium strains resistant to multiple antibiotics illustrates the need to develop new approaches for treatment and prevention which will require a better understanding of the fundamental mechanisms by which this pathogen causes disease. The role of adhesins in colonizing intestinal surfaces has not been intensively studied in Salmonella but likely represents an important first step during infection. Our long-range goal is to understand the role adhesins play in Salmonella pathogenesis. The objectives of this application are to identify regulatory mechanisms that prevent expression of most adherence factors under standard laboratory growth conditions and to define their binding specificities. Our central hypothesis is that fimbrial and non-fimbrial adhesins from a group of functionally related adherence factors that act in concert during intestinal colonization by S. typhimurium. We plan to test different aspects of our hypothesis and accomplish the objectives of this application by pursuing the following specific aims: 1. Determine whether S. typhimurium adhesins are co-regulated. 2. Determine the binding specificities of S. typhimurium adhesins. The proposed work is innovative because it represents the first genomic analysis of the role of adherence determinants in Salmonella pathogenesis and uses novel approaches to study the regulation and the function of adhesins. It is our expectation that our approach will establish that many adhesins are coregulated and have similar or redundant functions, thus making them components of a complex virulence factor required for intestinal colonization and virulence. This outcome will be significant since it will establish a new paradigm in Salmonella pathogenesis that may be applicable to other enteric pathogens. Furthermore insight into the mechanisms of adherence in the intestine will facilitate the development of new and innovative approaches to treat or prevent infection.
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