Salmonella entericaSerovar Typhimurium RamA, Intracellular Oxidative Stress Response, and Bacterial Virulence

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Abstract
Escherichia coliandSalmonella entericaserovar Typhimurium have evolved genetic systems, such as thesoxR/SandmarAregulons, to detoxify reactive oxygen species, like superoxide, which are formed as by-products of metabolism. Superoxide also serves as a microbicidal effector mechanism of the host's phagocytes. Here, we investigate whether regulatory genes other thansoxR/SandmarAare active in response to oxidative stress inSalmonellaand may function as virulence determinants. We identified a bacterial gene, which was designatedramA(342 bp) and mapped at 13.1 min on theSalmonellachromosome, that, when overexpressed on a plasmid inE. coliorSalmonella, confers a pleiotropic phenotype characterized by increased resistance to the redox-cycling agent menadione and to multiple unrelated antibiotics. TheramAgene is present inSalmonellaserovars but is absent inE. coli.The gene product displays 37 to 52% homology to the transcriptional activatorssoxR/SandmarAand 80 to 100% identity to a multidrug resistance gene inKlebsiella pneumoniaeandSalmonella entericaserovar Paratyphi A. Although aramA soxR/Sdouble null mutant is highly susceptible to intracellular superoxide generated by menadione and displays decreased Mn-superoxide dismutase activity, intracellular survival of this mutant within macrophage-like RAW 264.7 cells and in vivo replication in the spleens in Ityrmice are not affected. We concluded that despite its role in the protective response of the bacteria to oxidative stress in vitro, the newly identifiedramAgene, together withsoxR/S, does not play a role in initial replication ofSalmonellain the organs of mice.