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The Specific Aims are as follows: Generation of S. flexneri 2a strains that carry mutations in each of multiple steps in pathogenesis and identification of additional genes involved in intracellular survival cell-to-cell spread. Characterization of the level of in vivo attenuation and reactogenicity of strains generated above. Definition of the steps in Shigella pathogenesis that are required for the induction of an adaptive immune response in vivo. Construction of targeted multiple deletion strains of Shigella and testing of these strains in animal models.
Shigella sp. causes an estimated 650,000 deaths and 200 million cases of dysentery or diarrhea annually. No effective and safe vaccine exists. Disease due to Shigella involves bacterial uptake by M cells and invasion of colonic enterocytes, followed by lysis of the phagocytic vacuole with release of the bacterium into the cytoplasm, where it assembles actin tails to move and spread directly into adjacent cells. Despite the intracellular localization of Shigella during certain steps in the disease process, others and we have shown that adaptive immunity is mediated by antibody. Naturally acquired immunity is at least partially serotype-specific and largely independent of T lymphocytes. Thus, an antibody response to bacterial lipopolysaccharide appears to be essential. However, while certain classes of mutant Shigella have been shown to not induce adaptive immunity, the specific steps in pathogenesis that are essential to its development are not known. Further elucidation of those steps in pathogenesis that are essential to the development of adaptive immunity will permit a more logical development of optimally attenuated candidate vaccine strains. The Specific Aims are as follows: Generation of S. flexneri 2a strains that carry mutations in each of multiple steps in pathogenesis and identification of additional genes involved in intracellular survival cell-to-cell spread. Characterization of the level of in vivo attenuation and reactogenicity of strains generated above. Definition of the steps in Shigella pathogenesis that are required for the induction of an adaptive immune response in vivo. Construction of targeted multiple deletion strains of Shigella and testing of these strains in animal models. Data obtained from these approaches should permit a more logical design of Shigella vaccine strains. This proposal specifically addresses the goal for Shigella research within PA-97-053 of April 11, 1997.