The purine biosynthesis regulator PurR moonlights as a virulence regulator in Staphylococcus aureus

William E. Sause, Divya Balasubramanian, Irnov Irnov, Richard Copin, Mitchell J. Sullivan, Alexis Sommerfield, Rita Chan, Avantika Dhabaria, Manor Askenazi, Beatrix Ueberheide, Bo Shopsin, Harm Van Bakel, Victor J. Torres

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

The pathogen Staphylococcus aureus colonizes and infects a variety of different sites within the human body. To adapt to these different environments, S. aureus relies on a complex and finely tuned regulatory network. While some of these networks have been well-elucidated, the functions of more than 50% of the transcriptional regulators in S. aureus remain unexplored. Here, we assess the contribution of the LacI family of metabolic regulators to staphylococcal virulence. We found that inactivating the purine biosynthesis regulator purR resulted in a strain that was acutely virulent in bloodstream infection models in mice and in ex vivo models using primary human neutrophils. Remarkably, these enhanced pathogenic traits are independent of purine biosynthesis, as the purR mutant was still highly virulent in the presence of mutations that disrupt PurR’s canonical role. Through the use of transcriptomics coupled with proteomics, we revealed that a number of virulence factors are differentially regulated in the absence of purR. Indeed, we demonstrate that PurR directly binds to the promoters of genes encoding virulence factors and to master regulators of virulence. These results guided us into further ex vivo and in vivo studies, where we discovered that S. aureus toxins drive the death of human phagocytes and mice, whereas the surface adhesin FnbA contributes to the increased bacterial burden observed in the purR mutant. Thus, S. aureus repurposes a metabolic regulator to directly control the expression of virulence factors, and by doing so, tempers its pathogenesis.

Original languageEnglish
Pages (from-to)13563-13572
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number27
DOIs
StatePublished - 2019

Keywords

  • Infection
  • MRSA
  • Pathogenesis
  • PurR
  • Purine biosynthesis

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