The expression of virulence determinants is tightly regulated so that they are produced at the right time and place during infection. Bacterial pathogens typically rely on two-component systems to modulate gene expression in response to environmental cues. The PhoP/PhoQ two- component system is the master regulator of Salmonella pathogenicity by governing the production of virulence proteins that are required in different tissues and cellular compartments. The PhoQ protein is a sensor for extracytoplasmic Mg2+ that controls the phosphorylated state of the PhoP protein, a transcription factor whose has higher affinity for its target DNAs when phosphorylated. We have determined that the activation of the PhoP/PhoQ system is transient despite the continuous presence ofInducing signals, and that the PhoP protein can regulate transcription from a wide variety of promoters. This proposal describes experiments aimed at understanding how the PhoP/PhoQ system is controlled, how the PhoP protein regulates transcription from different classes of promoters and in conjunction with other regulatory proteins, and to determine the virulence significance of PhoP-mediated expression of other regulatory proteins, such as SlyA and SsrB, that are required for Salmonella's ability to survive in ma crophages. An accomplishment of these goals will take us closer to understanding the mechanisms by which a microbe can modify its gene expression repertoire in response to environmental cues. Moreover, they will help the study of other pathogenic organisms and other two-component systems because the PhoP/PhoQ system is necessary for virulence in Yersinia spp. and Shigellaflexneri, and because the biochemical activities of two-component systems are largely conserved.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049561-18
Application #
7795860
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Alexander, William A
Project Start
1992-02-01
Project End
2010-08-31
Budget Start
2010-04-01
Budget End
2010-08-31
Support Year
18
Fiscal Year
2010
Total Cost
$78,348
Indirect Cost
Name
Washington University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Yeom, Jinki; Wayne, Kyle J; Groisman, Eduardo A (2017) Sequestration from Protease Adaptor Confers Differential Stability to Protease Substrate. Mol Cell 66:234-246.e5
Pontes, Mauricio H; Yeom, Jinki; Groisman, Eduardo A (2016) Reducing Ribosome Biosynthesis Promotes Translation during Low Mg2+ Stress. Mol Cell 64:480-492
Kriner, Michelle A; Sevostyanova, Anastasia; Groisman, Eduardo A (2016) Learning from the Leaders: Gene Regulation by the Transcription Termination Factor Rho. Trends Biochem Sci 41:690-699
Park, Sun-Yang; Pontes, Mauricio H; Groisman, Eduardo A (2015) Flagella-independent surface motility in Salmonella enterica serovar Typhimurium. Proc Natl Acad Sci U S A 112:1850-5
Pontes, Mauricio H; Lee, Eun-Jin; Choi, Jeongjoon et al. (2015) Salmonella promotes virulence by repressing cellulose production. Proc Natl Acad Sci U S A 112:5183-8
Kriner, Michelle A; Groisman, Eduardo A (2015) The Bacterial Transcription Termination Factor Rho Coordinates Mg(2+) Homeostasis with Translational Signals. J Mol Biol 427:3834-49
Sevostyanova, Anastasia; Groisman, Eduardo A (2015) An RNA motif advances transcription by preventing Rho-dependent termination. Proc Natl Acad Sci U S A 112:E6835-43
Pontes, Mauricio H; Sevostyanova, Anastasia; Groisman, Eduardo A (2015) When Too Much ATP Is Bad for Protein Synthesis. J Mol Biol 427:2586-2594
Park, Sun-Yang; Groisman, Eduardo A (2014) Signal-specific temporal response by the Salmonella?PhoP/PhoQ regulatory system. Mol Microbiol 91:135-44
Zwir, Igor; Yeo, Won-Sik; Shin, Dongwoo et al. (2014) Bacterial nucleoid-associated protein uncouples transcription levels from transcription timing. MBio 5:e01485-14

Showing the most recent 10 out of 53 publications