The alternative sigma factor c^ plays a central role in Salmonella pathogenesis. In the initial project period, we have found that Salmonella mutants lacking aE 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 OE- dependent loci, demonstrated that OE interacts with the other four alternative sigma factors in Salmonella, and discovered that aE 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 OE activation and its stimulation of Salmonella Pathogenicity Island 2 (SPI-2) gene expression in response to acid pH; [3] Examine the complementary actions of aE and PspA in promoting resistance to antimicrobial peptides and the maintenance of proton motive force; [4] Assess the roles of specific oE-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 #
5R01AI044486-11
Application #
7750529
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Alexander, William A
Project Start
1998-12-01
Project End
2011-11-30
Budget Start
2010-01-01
Budget End
2011-11-30
Support Year
11
Fiscal Year
2010
Total Cost
$367,781
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
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
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
Fang, Ferric C; Frawley, Elaine R; Tapscott, Timothy et al. (2016) Bacterial Stress Responses during Host Infection. Cell Host Microbe 20:133-43
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
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
Frawley, Elaine R; Fang, Ferric C (2014) The ins and outs of bacterial iron metabolism. Mol Microbiol 93:609-16
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
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

Showing the most recent 10 out of 42 publications