Determinants of Nitric Oxide Resistance in Staphylococcus aureus Public Deposited

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  • March 21, 2019
Creator
  • Grosser, Melinda
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Staphylococcus aureus is a prolific human pathogen capable of circumventing host innate immunity by resisting the antimicrobial radical nitric oxide (NO·). NO· is critical for the efficient clearance of a wide range of microbial pathogens but is largely ineffective in the clearance of S. aureus. The unique ability of S. aureus to resist NO· requires a multifaceted response to cope with the pleiotropic effects of NO·. We show that this response involves a unique regulatory scheme that precludes stress regulon induction and comprises central metabolic and virulence regulators, including SrrAB, Fur, SarA, CodY, and Rot. A second component of the S. aureus NO· response is the induction of an NO·-resistant metabolism. Specifically, NO·-mediated inhibition of respiration imposes a requirement for the fermentation of hexoses. We show that S. aureus has acquired unique carbohydrate transporters that facilitate maximal uptake of glucose and other host sugars to support its non-respiratory growth in inflamed tissue. Finally, to more comprehensively identify genes involved in NO· resistance, we used a Tn-Seq approach to quantify the fitness of ~76,000 unique S. aureus transposon mutants following prolonged NO· exposure in broth culture and passage through a murine model of skin and soft tissue infections (SSTIs). Our results indicate a comprehensive set of non-redundant genes essential for both NO· resistance and survival in murine SSTIs. Most notably, our Tn-Seq data suggests a novel role for the S. aureus F1F0 ATP synthase under these conditions. Altogether, our work provides a comprehensive view of the regulatory, metabolic, and genetic requirements for S. aureus NO· resistance, a highly unique trait that is central to S. aureus pathogenesis.
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Rights statement
  • In Copyright
Advisor
  • Braunstein, Miriam
  • Goldman, William
  • Kawula, Thomas
  • Richardson, Anthony
  • Jones, Corbin
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2016
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