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.
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