Adaptation of Intracellular Salmonella Enterica Serovar Typhimurium to Survival in the Host Environment

The bacterial pathogen Salmonella enterica serovar Typhimurium causes disease in many animals including all the most important farm species. In mice this bacterium causes a severe invasive disease which shares many features in common with invasive salmonellosis in other host species. Spread of S. typhimuium within the host is dependent upon the ability of the bacteria to survive within the phagosomes of infected macrophages and to disseminate via the blood to the liver and spleen where salmonellae can be found in large quantities. <P>
This project will investigate the hypothesis that survival of S. typhimurium within the phagosome of macrophages is dependent on changes in bacterial gene expression and that these changes may indicate genes that are thus also essential for colonisation and pathogenesis in whole animal infections. In order to address this hypothesis we will use DNA microarrays to analyse S. typhimurium gene expression from infected murine bone marrow derived macrophages. The macrophages will be taken from wild-type mice and those with defined genetic mutations involved in phagosomal regulation of bacterial survival. We will delete bacterial genes whose expression is elevated in wild-type macrophages in comparison with the mutant cells and explore how these deletions affect bacterial survival within host cells. <P>
We will also study whether the absence of these genes affects the host macrophage response to bacterial infection. Bacterial mutants that are attenuated within murine macrophages will then be tested in murine models of salmonellosis in wild-type animals to see if the survival of these mutants are altered in vivo. <P>
This project will identify novel salmonella genes that are altered during infection by integrating S. typhimurium gene analysis, from infected macrophages which lack genes involved in phagosome function, with functional studies on bacterial mutants. This will allow us the unique opportunity to also explore both the significance of, and the mechanisms underlying, bacterial resistance to the host response to infection.