It is our belief that control of iron homeostasis is crucial to the ability of Salmonella typhimufium to survive the oxidative and nitrosative stresses encountered within host macrophages, iron can interact with hydrogen peroxide to form highly toxic hydroxyl or ferryl radicals during the Fenton reaction. In confirmation of our idea that iron homeostasis is crucial for bacterial survival, a S. typhimurium fur mutant, which is deficient in its ability to down-regulate iron uptake, has increased intracellular iron and is more susceptible than wild type, to hydrogen peroxide, when grown in minimal medium. Surprisingly, this same mutant when grown in rich medium does not exhibit increased sensitivity as compared to wild type Salmonella, and in fact, had very similar iron content. These results suggested that a fur-independent mechanism exists to control intracellular iron levels. We have identified a candidate operon encoding putative transport proteins. It is the goal of this proposal to further characterize the yegMNOB operon and ascertain its role in controlling iron homeostasis, resistance to oxidative and nitrosative stresses, and virulence in the murine model. These studies will provide new insights into the mechanisms utilized by bacteria to control intracellular iron levels, and will further our understanding of the pathogenic mechanisms used by S. typhimurium to circumvent host defenses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32AI054052-01A1
Application #
6693521
Study Section
Special Emphasis Panel (ZRG1-F08 (20))
Program Officer
Van de Verg, Lillian L
Project Start
2003-07-01
Project End
2005-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
1
Fiscal Year
2003
Total Cost
$46,420
Indirect Cost
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Frawley, Elaine R; Crouch, Marie-Laure V; Bingham-Ramos, Lacey K et al. (2013) Iron and citrate export by a major facilitator superfamily pump regulates metabolism and stress resistance in Salmonella Typhimurium. Proc Natl Acad Sci U S A 110:12054-9
Karlinsey, Joyce E; Maguire, Michael E; Becker, Lynne A et al. (2010) The phage shock protein PspA facilitates divalent metal transport and is required for virulence of Salmonella enterica sv. Typhimurium. Mol Microbiol 78:669-85
Nairz, Manfred; Fritsche, Gernot; Crouch, Marie-Laure V et al. (2009) Slc11a1 limits intracellular growth of Salmonella enterica sv. Typhimurium by promoting macrophage immune effector functions and impairing bacterial iron acquisition. Cell Microbiol 11:1365-81
Nairz, Manfred; Theurl, Igor; Schroll, Andrea et al. (2009) Absence of functional Hfe protects mice from invasive Salmonella enterica serovar Typhimurium infection via induction of lipocalin-2. Blood 114:3642-51
Crouch, Marie-Laure V; Castor, Margaret; Karlinsey, Joyce E et al. (2008) Biosynthesis and IroC-dependent export of the siderophore salmochelin are essential for virulence of Salmonella enterica serovar Typhimurium. Mol Microbiol 67:971-83