Metabolic adaptation of Staphylococcus aureus to low-respiratory conditions encountered during invasive infection

Staphylococcus aureus is one of several Staphylococcus species that colonizes human skin. Several of these Staphylococcus species are also capable of causing human disease, including S. aureu. However, S. aureus infections occur far more frequently, exhibit greater variability in their presentation, and are generally much more severe. The widely recognized explanation for this observation is that S. aureu has acquired a large number of unique toxins and adhesins that promote enhanced tissue penetration and destruction. Our results support a complementary hypothesis: that S. aureu has metabolically adapted to invasive infection. Importantly, inflamed tissue spaces exhibit low levels of oxygen, low levels of free iron, and high levels of nitric oxide. These factors contribute to the inhibition of bacterial respiration. We show that S. aureu exhibits enhanced non-respiratory growth compared to other pathogenic Staphylococci and identify S. aureus acquisition of unique carbohydrate transporters and fermentative metabolic genes as the primary mechanism by which these divergent phenotypes have arisen. We then demonstrate that several of these unique metabolic genes contribute to S. aureu virulence in animal models of infection. Our data implicate metabolic adaptation to invasion infection as one mechanism responsible for the speciation of S. aureu from other skin-colonizing Staphylococci and implicate the host metabolic state as a contributing factor to S. aureu pathogenesis.