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 To illuminate its role in staphylococcal physiology, we initially assessed whether PhoPR controls the expression of the three inorganic phosphate (P) importers (PstSCAB, NptA, and PitA) in This analysis revealed that PhoPR is required for the expression of and and can modulate 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-limiting conditions, and in some environments, its primary role is to induce the expression of or Interestingly, in other environments, PhoPR is necessary for growth independent of P transporter expression, indicating that additional PhoPR-regulated factors promote adaptation to low-P conditions. Together, these data suggest that PhoPR differentially contributes to growth in an environment-specific manner. In a systemic infection model, a mutant of lacking PhoPR is highly attenuated. Further investigation revealed that PhoPR-regulated factors, in addition to P transporters, are critical for staphylococcal pathogenesis. Cumulatively, these findings point to an important role for PhoPR in orchestrating P acquisition as well as transporter-independent mechanisms that contribute to virulence.

Comparative transcriptomics reveals PrrAB-mediated control of metabolic, respiration, energy-generating, and dormancy pathways in Mycobacterium smegmatis

“…A prototypical TCS consists of a membrane-bound histidine kinase sensor and a cytoplasmic DNA-binding response regulator. In pathogenic bacteria, TCSs act as virulence factors that regulate diverse survival mechanisms, such as antibiotic resistance [7], phosphate limitation [8], low oxygen tension [9], and evasion of immune responses [10]. Though mammalian proteins bearing histidine kinase sequence motifs and activity [11] have been identified, response regulators appear absent in humans, opening the possibility for development of inhibitors targeting virulence-related or essential bacterial TCSs as novel therapeutic approaches.…”

Genes Influencing Phage Host Range in Staphylococcus aureus on a Species-Wide Scale

“…The PhoPR two-component system is responsible for regulating expression of phosphate uptake systems (ABC transporters) based on phosphate levels. In S. aureus , PhoPR is necessary for growth under phosphate-limiting conditions by regulating either phosphate transporters or other factors, depending on the environment ( 53 ). In Bacillus subtilis , the sensor kinase PhoR senses phosphate limitation through wall teichoic acid (WTA) intermediates ( 54 ) and correspondingly represses WTA biosynthesis gene expression ( 55 ).…”

Carprofen-induced depletion of proton motive force reverses TetK-mediated doxycycline resistance in methicillin-resistant Staphylococcus pseudintermedius

“…By these two alterations in metabolic adaptation to CPF bacterial cells lose the opportunity to overproduce NADH and ATP to compensate for PMF depletion. This is supported by the fact that the phosphate starvation regulator PhoP, which is normally expressed in response to a lack of inorganic phosphate 33 , was downregulated following exposure to CPF and DOX. Since ATP production decreases, there is no inorganic phosphate deficit.…”