Salmonellosis is one of the greatest causes of morbidity and mortality worldwide. Understanding this organism's mechanism of virulence is central to decreasing its ability to be a pathogen. Mechanisms used by Salmonella to permit infection are the capability to withstand environmental stresses that may damage its DNA and the ability to repair any ensuing damage to its genome. This makes the relationship between DNA repair and replication vital to the organism's survival. As an intracellular pathogen, Salmonella is subject to the host defenses of the macrophage- the respiratory burst and inducible nitric oxide system that produce reactive oxygen and nitrogen species. To characterize the mechanisms that Salmonella uses for repair of DNA damage by reactive oxygen and nitrogen species, strains of Salmonella will be constructed that are deficient in components of DNA repair and replication. These mutants will be characterized by their resistance to oxidative and nitrosative stress under laboratory conditions and in mice. These studies will produce insights into complex host-pathogen interactions for this important infection and provide new information on the biochemical interactions that reactive oxygen and nitrogen species have with DNA replication and repair.
