Salmonella infections represent a major health concern for both humans and domesticated animals in the US. The AIDS epidemic and the appearance of multidrug-resistant Salmonella strains have dramatically increased the impact of Salmonella infections worldwide. Salmonella is a pathogen that can cause both mucosal and systemic infections in susceptible hosts. A novel route for the extraintestinal dissemination of this enteric bacterium that depends on CD18(+) cells has been recently described by the applicant laboratory. The immunological significance of this route remains to be elucidated. The primary goal of the research described in this application is to explore the hypothesis that CD18(+) phagocytes transport S. typhimurium to extraintestinal sites for the initiation of systemic immune responses.
The specific aims are: 1) To further characterize the CD18(+) phagocytes that transport Salmonella extraintestinally. The activation, differentiation and antimicrobial nature of Salmonella-containing CD18(+) cells isolated from the bloodstream of orally infected mice will be characterized by flow cytometry, immunocytochemistry and microbiological plating techniques. The gastrointestinal location of contact between Salmonella and CD18(+) cells as well as the molecular basis for the transmigration of bacteria-containing phagocytes will also be explored. 2) To determine the immunogenic potential of Salmonella-containing CD18(+) phagocytes originating in the intestinal mucosa. The antigen-presenting capability of CD18(+) phagocytes carrying Salmonella, the subsets and T cell receptor (TCR) repertoires of the T cells stimulated by these phagocytes and the cytokines elicited during this process will be examined. 3) To study the effector mechanisms mediating immunity conferred by CD18(+) phagocytes. Protective immune responses elicited by grafting CD18(+) cells into control and mutant mice deficient in innate [e.g., NADPH phagocyte oxidase (phox), inducible nitric oxide synthase (iNos)] or acquired (e.g., perforin) immune function will be evaluated. A better understanding of the fundamental processes linking mucosal and systemic immune responses in the well-characterized murine Salmonella model will ultimately provide new approaches for developing more effective treatments and safer vaccines for infectious diseases.
