The Salmonellae are enteroinvasive pathogens that cause a variety of diseases including gastroenteritis, bacteremia, and typhoid fever. The long-term objectives of this research are to understand, at the molecular level, the mechanisms by which Salmonella typhimurium circumvents the host immune system and causes disease. To understand the molecular basis of pathogenesis, the gene products that are specifically required for those processes must be identified and characterized. We have devised a genetic system that selects for Salmonella typhimurium genes that are specifically induced at some point during the infection. Using this system two previously uncharacterized genes that are specifically induced during intestinal colonization have been identified. Inactivation of one of these genes suggests that its product is specifically required for Salmonella typhimurium to efficiently colonize the mouse intestine. This gene does not play a role in the systemic stages of the disease process. The specific function of the virulence gene products in the host will be addressed by analyzing the effects of defined mutations in these genes on the infection process. The regulation of these virulence genes will be examined. This will include the identification of any trans-acting factors required for the induction of these genes in the host, as well as the internal host signals that elicit this regulation, and will be accomplished through a detailed genetic analysis of these operons using gene fusion technology. Biochemical analysis of the gene products will allow us to further define their specific role in pathogenesis. The incidence of salmonellosis in the US has significantly increased in the last decade. Indeed, the estimated annual cost of treatment and business losses due to Salmonella infections in the US is $4 billion. Salmonella infection is a common occurrence in patients with AIDS, and recurrent Salmonella bacteremia is an AIDS-defining illness. Increased understanding of the disease process will lead to better methods of prevention and treatment. The work proposed here has direct implications for vaccine development and antibiotic drug development and should provide information, not only about virulence mechanisms of the bacteria, but also the functions of the host designed to prevent bacterial infections.
