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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IDM-S (03))
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Alexander, William A
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University of Colorado Denver
Schools of Medicine
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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
Crawford, Matthew A; Henard, Calvin A; Tapscott, Timothy et al. (2016) DksA-Dependent Transcriptional Regulation in Salmonella Experiencing Nitrosative Stress. Front Microbiol 7:444
Crawford, Matthew A; Tapscott, Timothy; Fitzsimmons, Liam F et al. (2016) Redox-Active Sensing by Bacterial DksA Transcription Factors Is Determined by Cysteine and Zinc Content. MBio 7:e02161-15
Fang, Ferric C; Frawley, Elaine R; Tapscott, Timothy et al. (2016) Bacterial Stress Responses during Host Infection. Cell Host Microbe 20:133-43
Vázquez-Torres, Andrés; Bäumler, Andreas J (2016) Nitrate, nitrite and nitric oxide reductases: from the last universal common ancestor to modern bacterial pathogens. Curr Opin Microbiol 29:1-8
Jones-Carson, Jessica; Husain, Maroof; Liu, Lin et al. (2016) Cytochrome bd-Dependent Bioenergetics and Antinitrosative Defenses in Salmonella Pathogenesis. MBio 7:
Fang, Ferric C; Frawley, Elaine R; Tapscott, Timothy et al. (2016) Discrimination and Integration of Stress Signals by Pathogenic Bacteria. Cell Host Microbe 20:144-53
Austin, C R; Goodyear, A W; Bartek, I L et al. (2015) A Burkholderia pseudomallei colony variant necessary for gastric colonization. MBio 6:
Henard, Calvin A; Tapscott, Timothy; Crawford, Matthew A et al. (2014) The 4-cysteine zinc-finger motif of the RNA polymerase regulator DksA serves as a thiol switch for sensing oxidative and nitrosative stress. Mol Microbiol 91:790-804
Husain, Maroof; Jones-Carson, Jessica; Liu, Lin et al. (2014) Ferric uptake regulator-dependent antinitrosative defenses in Salmonella enterica serovar Typhimurium pathogenesis. Infect Immun 82:333-40

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