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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Special Emphasis Panel (ZAI1)
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University of Nebraska Medical Center
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Lehman, McKenzie K; Bose, Jeffrey L; Sharma-Kuinkel, Batu K et al. (2015) Identification of the amino acids essential for LytSR-mediated signal transduction in Staphylococcus aureus and their roles in biofilm-specific gene expression. Mol Microbiol 95:723-37
Hanamsagar, Richa; Aldrich, Amy; Kielian, Tammy (2014) Critical role for the AIM2 inflammasome during acute CNS bacterial infection. J Neurochem 129:704-11
Scherr, Tyler D; Lindgren, Kevin E; Schaeffer, Carolyn R et al. (2014) Mouse model of post-arthroplasty Staphylococcus epidermidis joint infection. Methods Mol Biol 1106:173-81
Heim, Cortney E; Vidlak, Debbie; Scherr, Tyler D et al. (2014) Myeloid-derived suppressor cells contribute to Staphylococcus aureus orthopedic biofilm infection. J Immunol 192:3778-92
Hernandez, Frank J; Huang, Lingyan; Olson, Michael E et al. (2014) Noninvasive imaging of Staphylococcus aureus infections with a nuclease-activated probe. Nat Med 20:301-6
Zurek, Oliwia W; Nygaard, Tyler K; Watkins, Robert L et al. (2014) The role of innate immunity in promoting SaeR/S-mediated virulence in Staphylococcus aureus. J Innate Immun 6:21-30
Kiedrowski, Megan R; Crosby, Heidi A; Hernandez, Frank J et al. (2014) Staphylococcus aureus Nuc2 is a functional, surface-attached extracellular nuclease. PLoS One 9:e95574
Sapp, April M; Mogen, Austin B; Almand, Erin A et al. (2014) Contribution of the nos-pdt operon to virulence phenotypes in methicillin-sensitive Staphylococcus aureus. PLoS One 9:e108868
Olson, Michael E; Todd, Daniel A; Schaeffer, Carolyn R et al. (2014) Staphylococcus epidermidis agr quorum-sensing system: signal identification, cross talk, and importance in colonization. J Bacteriol 196:3482-93
Lindgren, J K; Thomas, V C; Olson, M E et al. (2014) Arginine deiminase in Staphylococcus epidermidis functions to augment biofilm maturation through pH homeostasis. J Bacteriol 196:2277-89

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