Salmonella serotypes are the leading cause of food-borne infections with lethal outcome in the United States. The role of fimbrial 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 of fimbrial adhesins in Salmonella pathogenesis. The objectives of this application are to determine the effect of fimbrial phase variation on bacterial populations (in vitro and in vivo) and to define the contribution of these phase variable antigens to virulence using the mouse typhoid and bovine enterocolitis models. Our central hypothesis is that phase variation is an immune evasion mechanism of a group of functionally related fimbrial antigens that act in concert during intestinal colonization by S. typhimurium. This hypothesis has been formulated based on strong preliminary data, which suggest that (i) fimbriae elicit an adaptive immune response that can be evaded by phase variation, (ii) the S. typhimurium genome contains a large number of fimbrial operons that are regulated by phase variation, and (iii) simultaneous inactivation of multiple fimbrial operons has a synergistic effect on virulence. The rationale for the proposed research is that a better understanding of factors involved in intestinal adherence will likely provide new insights into mechanisms of tissue tropism, host range and disease caused by S. typhimurium that are required for new and innovative approaches to prevention and treatment. We plan to test different aspects of our hypothesis by pursuing the following four specific aims: (1) Determine the consequences of fimbrial phase variation on the heterogeneity of a S. typhimurium culture; (2) Determine the serological response to fimbrial subunits; (3) Determine the effect of an immune response elicited by vaccination with fimbrial subunits on S. typhimurium virulence; (4) Determine the role of fimbrial operons during intestinal colonization. It is our expectation that our approach will establish that fimbrial adhesins are components of a complex virulence factor required for intestinal colonization. This outcome will be significant since it will establish a new paradigm in Salmonella pathogenesis. The research will be of additional significance since it will shed light on the role of adherence in the pathogenesis of enterocolitis, a disease syndrome that is common in the US but only poorly understood because most investigators rely on a typhoid fever model to study virulence mechanisms.
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