Salmonellosis represents a serious global problem. The incidence of infection continues to increase worldwide, despite expensive research and changes at the production and processing levels. Our long term goal is to control Salmonella infection in humans and animals and to develop Salmonella-based vaccines to deliver heterologous antigens. Our objective, as outlined in this proposal, is to elucidate the genetic regulation of Salmonella genes whose products are required invasion. When Salmonella bacteria invade a host cell, they secrete effector proteins via a type III secretion system that are translocated into the host cell. Importantly, this secretion system has been shown to be an effective delivery system of viral epitopes to the host cell cytosol, hence it is being developed for use in vaccines against viral antigens and tumor-specific antigens. Understanding the regulation of the genes involved in type III secretion will enable us to design efficacious vaccine strains which will optimally deliver heterologous antigens. Specifically we will (i) identify genes which encode proteins regulating the invA gene (invasion regulator; inr genes), (ii) determine if the Inr proteins regulation other invasion genes encoded in the Salmonella pathogenicity island I, and (iii) identify other genes regulated by Inr and determine fi they are required for virulence of Salmonella. Our approach will involve using a variety of genetic and molecular biology techniques to identify mutants that show an altered expression of the invasion genes. These mutants will be used to identify additional virulence genes in Salmonella. Mutants generated in this study will be evaluated using tissue cultured and animal models.
