The primary objectives of this project are to provide greater insight into the control of eDNA generation (through autolysis) and processing (via staphylococcal nuclease) within a biofilm. These studies will focus on the varied micro-niches that exist within a staphylococcal biofilm, and define the metabolic and stoichiometric factors that influence the expression of genes involved in these processes during biofilm development. The proposed studies will extend our preliminary results testing the hypothesis that S. aureus biofilm produces distinct functional subpopulations in response to environmental and stochastic effects on gene expression. In testing this hypothesis we will establish and elucidate the functional roles of different functional subpopulations within a mature biofilm. To achieve these goals, we will perform three specific aims.
The first aim will utilize a variety of transcriptional and metabolic probes, in combination with BioFlux microfluidics technology, to investigate the metabolic heterogeneity that arises during biofilm development and its impact on death and lysis.
The second aim will study the regulation of nuclease expression during biofilm development, focusing heavily on the role of the Sae regulatory system, and the novel hypothesis that SaeP is a sensor of eDNA.
The third aim will establish a division of labor within a biofilm and define the functional roles of the different subpopulations within a biofilm, includig dispersal, mutagenesis, and antibiotic tolerance. Overall, the experiments described in these specific aims will rely on a highly collaborative effort to yield greater insight into the environmental and stochastic regulatory mechanisms that dictate the metabolism of different biofilm niches. In addition to providing a more complete understanding of the metabolic processes inherent to staphylococcal biofilm, this project will foster a burgeoning perspective of bacterial biofilm as a highly complex population of differentiated cells, akin to multicellular organisms.
As a leading cause of indwelling medical device-related infections, the study of Staphylococcus aureus biofilm formation and its impact on its host is critical to reducing the burden of this pervasive pathogen to our healthcare system. The collaborative efforts of our studies seek to identify the mechanisms responsible for the alteration of the host immune response to favor an anti-inflammatory environment that is more permissive for bacterial persistence. Overall, the results of these studies hold promise for the development of improved strategies to treat S. aureus biofilm-related infections.
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|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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