Salmonella enterica represents a considerable burden to human and animal health worldwide. A significant effort has been made to understand the pathogenesis of this intracellular pathogen and the host factors that mediate host defense. Clinical and experimental evidence have unequivocally demonstrated that CD4+ T cells and IFN3 are critical for preventing systemic disease by non-typhoidal Salmonella. IFN3 likely exerts diverse functions in resistance to this intracellular bacterium, including the activation of the antimicrobial arsenal of macrophages. Recent studies have indicated that IFN3 synergizes with Salmonella ligands to enhance the transcription of iNOS. The resultant high NO synthesis mediates most of the profound and long-lasting anti-Salmonella activity of IFN3-primed macrophages. The molecular mechanism(s) by which IFN3- activated NO synthesis enhances the anti-Salmonella activity of macrophages remains, however, largely unknown. We have generated biochemical and genetic evidence in support of a model in which C203 of the SsrB response regulator that mediates global Salmonella pathogenicity island 2 (SPI2) transcription is an important target of reactive nitrogen species (RNS). The goal of this application is to identify the molecular mechanisms underlying the RNS-mediated repression of SPI2 transcription. It is hypothesized that NO congeners repress SPI2 transcription by S-nitrosylating (-SNO) C203 of the dimerization domain of the SsrB response regulator. Specifically, we propose to 1) determine the RNS-mediated modifications that inactivate SsrB regulatory functions;2) examine SPI2 function in the context of Salmonella antinitrosative defenses;3) select for ssrB variant alleles that render SsrB signaling insensitive to RNS;and 4) characterize SsrB residues critical for dimerization.
Salmonella enterica represents a considerable burden to human and animal health worldwide. The mechanisms underlying the pathogenesis of salmonellosis are incompletely understood. The proposed research will shed light on the host pathogen interactions that modulate the expression of a virulence factors key to the ability of Salmonella to cause human disease.
|Fitzsimmons, Liam F; Liu, Lin; Kim, Ju-Sim et al. (2018) Salmonella Reprograms Nucleotide Metabolism in Its Adaptation to Nitrosative Stress. MBio 9:|
|Vázquez-Torres, Andrés (2018) Less Is Best in the Convergent Evolution of Typhoidal Salmonella. Cell Host Microbe 23:151-153|
|Shaw, Jeff A; Henard, Calvin A; Liu, Lin et al. (2018) Salmonella enterica serovar Typhimurium has three transketolase enzymes contributing to the pentose phosphate pathway. J Biol Chem 293:11271-11282|
|Tapscott, Timothy; Kim, Ju-Sim; Crawford, Matthew A et al. (2018) Guanosine tetraphosphate relieves the negative regulation of Salmonella pathogenicity island-2 gene transcription exerted by the AT-rich ssrA discriminator region. Sci Rep 8:9465|
|Kim, Ju-Sim; Liu, Lin; Fitzsimmons, Liam F et al. (2018) DksA-DnaJ redox interactions provide a signal for the activation of bacterial RNA polymerase. Proc Natl Acad Sci U S A 115:E11780-E11789|
|Kao, Daniel J; Saeedi, Bejan J; Kitzenberg, David et al. (2017) Intestinal Epithelial Ecto-5'-Nucleotidase (CD73) Regulates Intestinal Colonization and Infection by Nontyphoidal Salmonella. Infect Immun 85:|
|Bourret, Travis J; Liu, Lin; Shaw, Jeff A et al. (2017) Magnesium homeostasis protects Salmonella against nitrooxidative stress. Sci Rep 7:15083|
|Song, Miryoung; Kim, Ju-Sim; Liu, Lin et al. (2016) Antioxidant Defense by Thioredoxin Can Occur Independently of Canonical Thiol-Disulfide Oxidoreductase Enzymatic Activity. Cell Rep 14:2901-11|
|Jarrett, Michael J; Vázquez-Torres, Andres; Frank, Daniel N et al. (2016) Influence of Gelatin-Thrombin Matrix Tissue Sealant on Bacterial Colony Formation and Risk of Pelvic Infection. Infect Dis Obstet Gynecol 2016:2649708|
|Jones-Carson, Jessica; Husain, Maroof; Liu, Lin et al. (2016) Cytochrome bd-Dependent Bioenergetics and Antinitrosative Defenses in Salmonella Pathogenesis. MBio 7:|
Showing the most recent 10 out of 37 publications