PhoPR Contributes to Staphylococcus aureus Growth during Phosphate Starvation and Pathogenesis in an Environment-Specific Manner

Abstract

Microbial pathogens must obtain all essential nutrients, including phosphate, from the host. To optimize phosphate acquisition in diverse and dynamic environments, such as mammalian tissues, many bacteria use the PhoPR two-component system. Despite the necessity of this system for virulence in several species, PhoPR has not been studied in the major human pathogen Staphylococcus aureus To illuminate its role in staphylococcal physiology, we initially assessed whether PhoPR controls the expression of the three inorganic phosphate (P_i) importers (PstSCAB, NptA, and PitA) in S. aureus This analysis revealed that PhoPR is required for the expression of pstSCAB and nptA and can modulate pitA expression. Consistent with a role in phosphate homeostasis, PhoPR-mediated regulation of the transporters is influenced by phosphate availability. Further investigations revealed that PhoPR is necessary for growth under P_i-limiting conditions, and in some environments, its primary role is to induce the expression of pstSCAB or nptA Interestingly, in other environments, PhoPR is necessary for growth independent of P_i transporter expression, indicating that additional PhoPR-regulated factors promote S. aureus adaptation to low-P_i conditions. Together, these data suggest that PhoPR differentially contributes to growth in an environment-specific manner. In a systemic infection model, a mutant of S. aureus lacking PhoPR is highly attenuated. Further investigation revealed that PhoPR-regulated factors, in addition to P_i transporters, are critical for staphylococcal pathogenesis. Cumulatively, these findings point to an important role for PhoPR in orchestrating P_i acquisition as well as transporter-independent mechanisms that contribute to S. aureus virulence.

Keywords: NptA; PhoPR; PstSCAB; Staphylococcus aureus; infection; infectious disease; phosphate homeostasis; two-component system.