Complete Title of Thesis: "DksA-mediated Resistance of Salmonella against Oxidative and Nitrosative Stress"
Prepared under the direction of: Andres Vazquez-Torres
Many of the over 2,500 serovars of Salmonella enterica cause significant morbidity and mortality worldwide. Non-typhoidal Salmonella residing in the gastrointestinal tract of wild and domestic animals are transmitted to humans after consumption of contaminated food or water. Non-typhoidal Salmonella primarily cause gastroenteritis; however, these serovars can disseminate to systemic sites in immunocompromised individuals with low CD4+ T cell counts or defects in IFNγ signaling. The species S. enterica also includes the human-adapted serovars Typhi and Paratyphi that cause life-threatening typhoid fever. Upon reaching the intestine, Salmonella invade enterocytes and specialized M-cells in Peyer's patches, or are taken up from the lumen by phagocytic cells. Salmonella have affinity for macrophages populating gut-associated lymphoid tissue and systemic sites. The ability of Salmonella to survive and replicate within macrophages is a hallmark of the pathogenesis of these intracellular bacteria. Intracellular Salmonella are exposed to a plethora of toxic species derived from superoxide and nitric oxide, which are synthesized by NADPH phagocyte oxidase and inducible NO synthase enzymatic complexes, respectively. Although many bacteria are killed in the harsh intracellular environment of macrophages, some Salmonella survive the onslaught. How do Salmonella survive inside cells of the innate host defense system under such hostile conditions? This thesis presents a novel molecular mechanism used by Salmonella to sense and respond to reactive species encountered at various phases during the infectious cycle. Investigations presented here show that the DksA stringent regulatory protein recognizes both oxyradicals and nitrogen oxides produced during the innate response of macrophages and elicits antioxidant and antinitrosative defenses at the transcriptional level. The DksA-mediated control of antioxidant and antinitrosative defenses is crucial for Salmonella intracellular survival by protecting against host-derived NADPH phagocyte oxidase and inducible nitric oxide synthase enzymatic activities, thereby contributing to Salmonella virulence.