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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Special Emphasis Panel (ZAI1)
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University of Nebraska Medical Center
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