| dc.description.abstract | Human food-borne pathogen Salmonella enterica ser. Typhimurium has evolved a sophisticated way to avoid the host immune response. Salmonella Typhimurium possesses various virulence factors to ensure successful colonization and persistence in the host, including but not limited to, fimbria, Type 3 Secretion Systems (T3SS-1 and T3SS-2), lipopolisaccharides (LPS), and flagella. Unlike many other bacteria, Salmonella can not only survive inside macrophages, but also replicate within these host cells. This strategy allows bacteria to stay invisible to the host immune system. Intracellular Salmonella can be detected by the host through flagellin recognition by Nod-like receptors (NLRs). NLRs in turn trigger Caspase-1 activation, which ultimately triggers pyroptosis of the host cell (Miao et al., 2011). While sufficiently replicated intracellular Salmonella utilizes pyroptosis to be released from the macrophage to infect other host cells, premature activation of pyroptosis could be detrimental for intracellular Salmonella in vivo. In defense, Salmonella downregulates expression of flagellins through activation of T3SS-2 encoded on SPI (Salmonella Pathogenicity Island)-2. The goal of this project was to identify Salmonella single deletion mutants that can produce flagella despite SPI-2 activation in order to expand our knowledge of genetic determinants involved in evasion of premature pyroptosis by S.Typhimurium .Screening of a library containing 2639 mutants, resulted in identification of 214 mutant candidates. We demonstrated that one of the mutants, identified and confirmed in our screen, ΔSTM1697, was expressing high levels of flagellin, despite expression of active T3SS-2. ΔSTM1697, predicted to encode a protein with putative diguanylate cyclase/phosphodiesterase domain 2, could play a role in c-di-GMP (cyclic di-GMP) metabolism. C-di-GMP is bacterial second messenger involved in control of motility/sessility lifestyle of S. Typhimurium. Identification of gene products, such as STM1697, involved in protection of Salmonella Typhimurium against premature detection by host innate immune system during growth in macrophages will stimulate a search for therapeutic targets to fight typhoid fever. | |
