The alternative sigma factor sigmaE plays a central role in Salmonella pathogenesis. In the initial project period, we have found that Salmonella mutants lacking sigmaE exhibit enhanced susceptibility to oxidative stress and antimicrobial peptides, reduced acid tolerance, deficient expression of virulence genes, impaired survival in phagocytic cells and markedly diminished virulence in mice. Furthermore we have identified novel sigmaE-dependent loci, demonstrated that sigmaE interacts with the other four alternative sigma factors in Salmonella, and discovered that sigmaE complements the actions of the phage shock (psp) response in maintaining proton motive force. In this competing renewal application, our specific aims are to: [1] Comprehensively characterize the regulatory networks interconnecting the alternative sigma factors of Salmonella; [2] Analyze the mechanism of sigmaE activation and its stimulation of Salmonella Pathogenicity Island 2 (SPI-2) gene expression in response to acid pH; [3] Examine the complementary actions of sigmaE and PspA in promoting resistance to antimicrobial peptides and the maintenance of proton motive force; [4] Assess the roles of specific sigmaE -dependent genes in resistance to acid pH, oxidative stress, antimicrobial peptides and virulence. Recent work in our laboratory and many others has revealed the enormous complexity and interconnectedness of bacterial regulatory networks. Through the proposed studies, we hope to provide a detailed mechanistic understanding of one of the most important regulatory pathways in Salmonella and to reveal novel insights into its physiologic functions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI044486-07A1
Application #
7033244
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Alexander, William A
Project Start
1998-12-01
Project End
2010-12-31
Budget Start
2006-01-15
Budget End
2006-12-31
Support Year
7
Fiscal Year
2006
Total Cost
$388,750
Indirect Cost
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Pando, Jasmine M; Karlinsey, Joyce E; Lara, Jimmie C et al. (2017) The Rcs-Regulated Colanic Acid Capsule Maintains Membrane Potential in Salmonella enterica serovar Typhimurium. MBio 8:
Singletary, Larissa A; Karlinsey, Joyce E; Libby, Stephen J et al. (2016) Loss of Multicellular Behavior in Epidemic African Nontyphoidal Salmonella enterica Serovar Typhimurium ST313 Strain D23580. MBio 7:e02265
Kinkel, Traci L; Ramos-Montañez, Smirla; Pando, Jasmine M et al. (2016) An essential role for bacterial nitric oxide synthase in Staphylococcus aureus electron transfer and colonization. Nat Microbiol 2:16224
Fang, Ferric C; Frawley, Elaine R; Tapscott, Timothy et al. (2016) Bacterial Stress Responses during Host Infection. Cell Host Microbe 20:133-43
Fang, Ferric C; Frawley, Elaine R; Tapscott, Timothy et al. (2016) Discrimination and Integration of Stress Signals by Pathogenic Bacteria. Cell Host Microbe 20:144-153
Nairz, Manfred; Ferring-Appel, Dunja; Casarrubea, Daniela et al. (2015) Iron Regulatory Proteins Mediate Host Resistance to Salmonella Infection. Cell Host Microbe 18:254-61
Nairz, Manfred; Schroll, Andrea; Haschka, David et al. (2015) Lipocalin-2 ensures host defense against Salmonella Typhimurium by controlling macrophage iron homeostasis and immune response. Eur J Immunol 45:3073-86
Fang, Ferric C; Weiss, Günter (2014) Iron ERRs with Salmonella. Cell Host Microbe 15:515-6
Velayudhan, Jyoti; Karlinsey, Joyce E; Frawley, Elaine R et al. (2014) Distinct roles of the Salmonella enterica serovar Typhimurium CyaY and YggX proteins in the biosynthesis and repair of iron-sulfur clusters. Infect Immun 82:1390-401
Frawley, Elaine R; Fang, Ferric C (2014) The ins and outs of bacterial iron metabolism. Mol Microbiol 93:609-16

Showing the most recent 10 out of 43 publications