The investigators propose using attenuated Salmonella typhimurium in mice as a model for investigation of 6 different avenues designed to enhance immune responses to foreign antigens expressed by bacterial vectors. The proposed approaches include engineering Salmonella to have an """"""""enhanced"""""""" RpoS+ phenotype, specifically decreasing immune response to immunodominant Salmonella antigens in an attempt to """"""""upregulate"""""""" responses against vectored foreign antigens, investigating the influence of attenuating mechanisms on immune responses to heterologous antigens, improve presentation of T-cell epitopes, investigating mechanisms of enhanced antigen delivery via """"""""self-lysing"""""""" bacterial vectors or """"""""runaway"""""""" plasmids which hyperexpress antigen in vivo, and lastly investigate the immunogenicity of DNA delivered by attenuated Salmonellae. The investigators will use heterologous bacterial antigens, and evaluate strains constructed in mice to assess mucosal, humoral and cellular immunity after oral vaccinations. As improved antigen delivery systems are discovered, it is anticipated that they will construct S. typhi or S. paratyphi A derivatives thereof for eventual clinical studies in humans.
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