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

Proceedings of the National Academy of Sciences of the United States of America 2019 Jul 02

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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.

Citation

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. The purine biosynthesis regulator PurR moonlights as a virulence regulator in Staphylococcus aureus. Proceedings of the National Academy of Sciences of the United States of America. 2019 Jul 02;116(27):13563-13572