Staphylococcus aureus has the ability to adhere and cause infections in a wide variety of niches within a human host. The overall hypothesis of this project is that S. aureus must fine-tune its central metabolism for rapid adaptation to different carbon and nitrogen sources available within a given tissue microenvironment. Previous work from our laboratory found that Staphylococcus aureus synthesizes arginine from proline instead of the highly conserved and well-characterized arginine biosynthetic pathway via glutamate. Further studies from Project #4 of this PPG have found that chronic biofilm-based infections are typified by an extensive myeloid-derived suppressor cell (MDSC) infiltrate and M2 macrophage polarization;both cell populations utilize extracellular arginine as a substrate for arginase, which redirects the metabolism of arginine to ornithine and the formation of polyamines, proline and subsequent collagen synthesis. Based on these data, we have developed a model whereby extracellular arginine is limited in a chronic infection. Thus, specifically, we propose that the metabolic pathways connecting proline and arginine synthesis via the urea cycle are critical to establishing a chronic infection. This application has the following specific aims: (i) define the innate immune response in the mouse renal abscess model (ii) investigate regulation of arginine biosynthesis in S. aureus and determine its importance in a mouse renal abscess model, (iii) interrogate function of urease in the establishment and maturation of S. aureus renal abscesses. A greater understanding of staphylococcal metabolism in vivo is required to develop novel antibacterial agents that target specific metabolic pathways and disrupt critical nutrient acquisition pathways.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
2P01AI083211-06
Application #
8742805
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Type
DUNS #
City
Omaha
State
NE
Country
United States
Zip Code
68198
Yamada, Kelsey J; Kielian, Tammy (2018) Biofilm-Leukocyte Cross-Talk: Impact on Immune Polarization and Immunometabolism. J Innate Immun :1-9
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Heim, Cortney E; Vidlak, Debbie; Odvody, Jessica et al. (2018) Human prosthetic joint infections are associated with myeloid-derived suppressor cells (MDSCs): Implications for infection persistence. J Orthop Res 36:1605-1613
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Markley, John L; Br├╝schweiler, Rafael; Edison, Arthur S et al. (2017) The future of NMR-based metabolomics. Curr Opin Biotechnol 43:34-40

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