PATHOGENESIS OF SALMONELLA DUBLIN INTESTINAL INFECTIONS

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Salmonella serovars are important causes of gastroenteritis and systemic disease worldwide. Non-typhoid Salmonella serovars associated with septicemia in people contain virulence plasmids encoding genes that promote dissemination of infection from the gastrointestinal tract. Virulence plasmids of S. typhimurium and S. dublin carry genes that increase resistance of the bacteria to both humoral and cellular components of the host defense. The rck gene encodes high level resistance to complement mediated killing, while the spv locus appears to enhance the ability of Salmonella to grow within cells of the reticuloendothelial system. The central theme of this Unit is that the plasmid-mediated virulence factors are expressed as specific responses to interactions between the bacteria and key components of the host defense system that operate in the intestine: complement, epithelial cells, macrophages, and gammadelta T cells. Specific bacterial control mechanisms are postulated to regulate rck and spv expression in response to environmental conditions in vivo. In addition, the host antibody response is postulated to down-regulate bacterial spv expression inside macrophages by a novel receptor-mediated mechanism. The Specific Aims are: 1) to determine the conditions which regulate expression of the plasmid-mediated complement resistance locus rck; 2) to define the molecular domains of Rck involved in complement resistance, and the interaction of Rck with complement components; 3) to determine the role of rck in complement resistance and virulence of wild-type strains; 4) to define host conditions that regulate expression of the plasmid- mediated virulence operon spv inside macrophages; 5) to determine whether spv genes are expressed in cultured epithelial cells; 6) to determine the role of gammadelta T cells in host resistance to Salmonella dublin strains with and without the spv locus. These studies follow closely the overall objective of the Program to characterize the role of intestinal host-environment interactions in host defense and the pathogenesis of disease.