Last Modified

• 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.

Date of publication

• August 2016

Keyword

• nitric oxide
• Tn-Seq
• bacterial metabolism
• Microbiology
• Staphylococcus aureus
• transcriptional regulation

DOI

• https://doi.org/10.17615/yzvv-0393

Resource type

• Dissertation

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

Language

• English

Parents:

This work has no parents.

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