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Glycolytic dependency of high-level nitric oxide resistance and virulence in Staphylococcus aureus.

ABSTRACT:

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Staphylococcus aureus is a prolific human pathogen capable of causing severe invasive disease with a myriad of presentations. The ability of S. aureus to cause infection is strongly linked with its capacity to overcome the effects of innate immunity, whether by directly killing immune cells or expressing factors that diminish the impact of immune effectors. One such scenario is the induction of lactic acid fermentation by S. aureus in response to host nitric oxide (NO·). This fermentative activity allows S. aureus to balance redox during NO·-induced respiration inhibition. However, little is known about the metabolic substrates and pathways that support this activity. Here, we identify glycolytic hexose catabolism as being essential for S. aureus growth in the presence of high levels of NO·. We determine that glycolysis supports S. aureus NO· resistance by allowing for ATP and precursor metabolite production in a redox-balanced and respiration-independent manner. We further demonstrate that glycolysis is required for NO· resistance during phagocytosis and that increased levels of extracellular glucose limit the effectiveness of phagocytic killing by enhancing NO· resistance. Finally, we demonstrate that S. aureus glycolysis is essential for virulence in both sepsis and skin/soft tissue models of infection in a time frame consistent with the induction of innate immunity and host NO· production.

Importance

Staphylococcus aureus is a leading human bacterial pathogen capable of causing a wide variety of diseases that, as a result of antibiotic resistance, are very difficult to treat. The frequency of S. aureus tissue invasion suggests that this bacterium has evolved to resist innate immunity and grow using the nutrients present in otherwise sterile host tissue. We have identified glycolysis as an essential component of S. aureus virulence and attribute its importance to promoting nitric oxide resistance and growth under low oxygen conditions. Our data suggest that diabetics, a patient population characterized by excess serum glucose, may be more susceptible to S. aureus as a result of increased glucose availability. Furthermore, the essential nature of S. aureus glycolysis indicates that a newly developed glycolysis inhibitor may be a highly effective treatment for S. aureus infections.

SUBMITTER: Vitko NP

PROVIDER: S-EPMC4453550 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Project description:UnlabelledThe ability of Staphylococcus aureus to resist host innate immunity augments the severity and pervasiveness of its pathogenesis. Nitric oxide (NO˙) is an innate immune radical that is critical for the efficient clearance of a wide range of microbial pathogens. Exposure of microbes to NO˙ typically results in growth inhibition and induction of stress regulons. S. aureus, however, induces a metabolic state in response to NO˙ that allows for continued replication and precludes stress regulon induction. The regulatory factors mediating this distinctive response remain largely undefined. Here, we employ a targeted transposon screen and transcriptomics to identify and characterize five regulons essential for NO˙ resistance in S. aureus: three virulence regulons not formerly associated with NO˙ resistance, SarA, CodY, and Rot, as well as two regulons with established roles, Fur and SrrAB. We provide new insights into the contributions of Fur and SrrAB during NO˙ stress and show that the S. aureus ΔsarA mutant, the most sensitive of the newly identified mutants, exhibits metabolic dysfunction and widespread transcriptional dysregulation following NO˙ exposure. Altogether, our results broadly characterize the regulatory requirements for NO˙ resistance in S. aureus and suggest an intriguing overlap between the regulation of NO˙ resistance and virulence in this well-adapted human pathogen.ImportanceThe prolific human pathogen Staphylococcus aureus is uniquely capable of resisting the antimicrobial radical nitric oxide (NO˙), a crucial component of the innate immune response. However, a complete understanding of how S. aureus regulates an effective response to NO˙ is lacking. Here, we implicate three central virulence regulators, SarA, CodY, and Rot, as major players in the S. aureus NO˙ response. Additionally, we elaborate on the contribution of two regulators, SrrAB and Fur, already known to play a crucial role in S. aureus NO˙ resistance. Our study sheds light on a unique facet of S. aureus pathogenicity and demonstrates that the transcriptional response of S. aureus to NO˙ is highly pleiotropic and intrinsically tied to metabolism and virulence regulation.

Project description:Staphylococcus aureus is a major human pathogen capable of causing a variety of diseases ranging from skin and soft tissue infections to systemic presentations such as sepsis, endocarditis, and osteomyelitis. For S. aureus to persist as a pathogen in these environments, it must be able to resist the host immune response, including the production of reactive oxygen and nitrogen species (e.g., nitric oxide, NO·). Extensive work from our lab has shown that S. aureus is highly resistant to NO·, especially in the presence of glucose. RNA-seq performed on S. aureus exposed to NO· in the presence and absence of glucose showed a new system important for NO· resistance-phosphate transport. The phosphate transport systems pstSCAB and nptA are both upregulated upon NO·-exposure, particularly in the presence of glucose. Both are key for phosphate transport at an alkaline pH, which the cytosol of S. aureus becomes under NO· stress. Accordingly, the ΔpstSΔnptA mutant is attenuated under NO stress in vitro as well as in macrophage and murine infection models. This work defines a new role in infection for two phosphate transporters in S. aureus and provides insight into the complex system that is NO· resistance in S. aureus.IMPORTANCEStaphylococcus aureus is a bacterial pathogen capable of causing a wide variety of disease in humans. S. aureus is unique in its ability to resist the host immune response, including the antibacterial compound known as nitric oxide (NO·). We used an RNA-sequencing approach to better understand the impact of NO· on S. aureus in different environments. We discovered that inorganic phosphate transport is induced by the presence of NO·. Phosphate is important for the generation of energy from glucose, a carbon source favored by S. aureus. We show that the absence of these phosphate transporters causes lowered energy levels in S. aureus. We find that these phosphate transporters are essential for S. aureus to grow in the presence of NO· and to cause infection. Our work here contributes significantly to our understanding of S. aureus NO· resistance and provides a new context in which S. aureus phosphate transporters are essential.

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Glycolytic dependency of high-level nitric oxide resistance and virulence in Staphylococcus aureus.

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