Disruption of phosphate homeostasis sensitizes staphylococcus aureus to nutritional immunity

Jessica L. Kelliher, Erin B. Brazel, Jana N. Radin, Eliot S. Joya, Paola K.Párraga Solórzano, Stephanie L. Neville, Christopher A. McDevitt, Thomas E. Kehl-Fie

Research output: Contribution to journalArticle

Abstract

To control infection, mammals actively withhold essential nutrients, including the transition metal manganese, by a process termed nutritional immunity. A critical component of this host response is the manganese-chelating protein calprotectin. While many bacterial mechanisms for overcoming nutritional immunity have been identified, the intersection between metal starvation and other essential inorganic nutrients has not been investigated. Here, we report that overexpression of an operon encoding a highly conserved inorganic phosphate importer, Pst-SCAB, increases the sensitivity of Staphylococcus aureus to calprotectin-mediated manganese sequestration. Further analysis revealed that overexpression of pst-SCAB does not disrupt manganese acquisition or result in overaccumulation of phosphate by S. aureus. However, it does reduce the ability of S. aureus to grow in phosphate-replete defined medium. Overexpression of pstSCAB does not aberrantly activate the phosphate-responsive two-component system PhoPR, nor was this two-component system required for sensitivity to manganese starvation. In a mouse model of systemic staphylococcal disease, a pstSCAB-overexpressing strain is significantly attenuated compared to wild-Type S. aureus. This defect is partially reversed in a calprotectin-deficient mouse, in which manganese is more readily available. Given that expression of pstSCAB is regulated by PhoPR, these findings suggest that overactivation of PhoPR would diminish the ability of S. aureus to resist nutritional immunity and cause infection. As PhoPR is also necessary for bacterial virulence, these findings imply that phosphate homeostasis represents a critical regulatory node whose activity must be precisely controlled in order for S. aureus and other pathogens to cause infection.

Original languageEnglish (US)
Article numbere00102
JournalInfection and immunity
Volume88
Issue number6
DOIs
StatePublished - Jun 1 2020

Keywords

  • Calprotectin
  • Infection
  • Manganese
  • Nutritional immunity
  • Phosphate homeostasis
  • Pstscab
  • Staphylococcus aureus

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

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  • Cite this

    Kelliher, J. L., Brazel, E. B., Radin, J. N., Joya, E. S., Solórzano, P. K. P., Neville, S. L., McDevitt, C. A., & Kehl-Fie, T. E. (2020). Disruption of phosphate homeostasis sensitizes staphylococcus aureus to nutritional immunity. Infection and immunity, 88(6), [e00102]. https://doi.org/10.1128/IAI.00102-20