Mechanisms Involved in Salmonella Immune Evasion

PROJECT SUMMARYSalmonella enterica is a significant cause of morbidity and mortality throughout the world. S. entericacauses acute gastroenteritis and is also responsible for systemic diseases that result in fatalinfections. Salmonella infection presents as intestinal outgrowth, penetration of the epithelial barrier,and subsequent uptake by macrophages, where Salmonella is ultimately trafficked to secondarylymphoid organs such as the spleen. S. enterica encodes two type three secretion systems encodedin the Salmonella pathogenicity islands 1 and 2 (SPI-1 and SPI-2) that are essential for cell invasionand intracellular survival, respectively. Regulation of virulence traits is an essential strategy for bacterial pathogens to cause disease.Ethanolamine is an abundant metabolite in the gastrointestinal (GI) tract and is also present in theintracellular environment. In the GI tract, the bacterial transcription factor EutR promotes expressionof genes encoding ethanolamine metabolism, which enables S. enterica to utilize ethanolamine as anenergy source and establish infection. During later stages of infection, EutR activates expression ofSPI-2 to enhance S. enterica survival within macrophages, and thus promote dissemination. AlthoughEutR is important for S. enterica disease progression, very little is known about EutR regulatorycircuits operative during infection or how these regulatory circuits influence S. enterica interaction withthe host. In Specific Aim 1, we will perform a detailed characterization of the role of EutR-dependentgene regulation in modulating host responses. In Specific Aim 2, we will elucidate EutR-regulatorycircuits operative during infection that influence disease outcome. These studies are important todeveloping new strategies to treat infectious diseases.