Shigella species, the causative agents of bacillary dysentery, are unique among enteric pathogens in the low infective dose required for disease. Whereas over 10(e)6 Vibrio cholera or 10(e)5 Salmonella species are required to produce disease, five hundred or less Shigella species are able to do so. All enteric pathogens must breach the acid barrier encountered in the stomach in order to reach the intestines. Recent research suggests that one explanation for the Shigella's low infective dose is that these organisms are better able to survive in an acidic environment than are other enteric pathogens. Although an understanding of how Shigella species survive an acidic environment will add to our knowledge of pathogenesis, this research could also have a significant impact on the development of live oral vaccines. Oral vaccines must be given in high dosage and administered with sodium bicarbonate to insure that an effective dose enters the intestines. The proposed research could lead to the construction of acid-resistant, oral vaccines strains which would be less costly to produce, simpler to administer, and more efficacious. The fact that shigellosis is confined to humans and higher primates make it impractical to test the relationship between infective dose and acid resistance in an animal model. S. typhimurium is a natural pathogen in mice however and this hypothesis could readily be tested in mice. The specific goals of this research are: 1) To identify Shigella genes, and gene products involved in the ability to survive an acidic environment using techniques of molecular biology. 2) To construct an acid resistant S. typhimurium by transferring acid resistant genes from Shigella species into S. typhimurium.
