Staphylococcus aureus Responds to the Central Metabolite Pyruvate To Regulate Virulence.

Lamia Harper,William E Sause,Adriana Heguy,Jessica Chapman,Aristotelis Tsirigos,Divya Balasubramanian,Desmond S Lun,Elizabeth A Ohneck,Tenzin Lhakhang,Jeffrey M Boyd,Bryan Mejia-Sosa,Beatrix Ueberheide,Victor J Torres,Anthony R Richardson,Paul Dunman

doi:10.1128/mbio.02272-17

Lamia Harper, William E Sause + Show 13 more

Open Access

https://doi.org/10.1128/mbio.02272-17

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Abstract

ABSTRACTStaphylococcus aureus is a versatile bacterial pathogen that can cause significant disease burden and mortality. Like other pathogens, S. aureus must adapt to its environment to produce virulence factors to survive the immune responses evoked by infection. Despite the importance of environmental signals for S. aureus pathogenicity, only a limited number of these signals have been investigated in detail for their ability to modulate virulence. Here we show that pyruvate, a central metabolite, causes alterations in the overall metabolic flux of S. aureus and enhances its pathogenicity. We demonstrate that pyruvate induces the production of virulence factors such as the pore-forming leucocidins and that this induction results in increased virulence of community-acquired methicillin-resistant S. aureus (CA-MRSA) clone USA300. Specifically, we show that an efficient “pyruvate response” requires the activation of S. aureus master regulators AgrAC and SaeRS as well as the ArlRS two-component system. Altogether, our report further establishes a strong relationship between metabolism and virulence and identifies pyruvate as a novel regulatory signal for the coordination of the S. aureus virulon through intricate regulatory networks.

Highlights

Staphylococcus aureus is a versatile bacterial pathogen that can cause significant disease burden and mortality
In S. aureus, one of the best-characterized two-component systems (TCSs) is the accessory gene regulator (Agr) quorum sensing system [10], which responds to changes in bacterial cell density to regulate gene expression [11], including that of the regulatory effector RNA known as RNAIII
In an attempt to determine what medium components may lead to this differential regulation, we investigated changes in the exoprotein profile of community-acquired methicillin-resistant S. aureus (CA-Methicillinresistant S. aureus (MRSA)) USA300, the predominant CA-MRSA linage in the United States [27], when grown in various laboratory media (Fig. 1)

Summary

Introduction

Staphylococcus aureus is a versatile bacterial pathogen that can cause significant disease burden and mortality. We show that pyruvate, a key nutrient and central metabolite, causes global changes to the metabolic flux of S. aureus and activates regulatory networks that allow significant increases in the production of leucocidins. These and other virulence factors are critical for S. aureus to infect diverse host niches, initiate infections, and effectively subvert host immune responses. Given its wide spectrum for routes of infection, S. aureus must be able to adapt to diverse and often hostile host environments by sensing environmental signals and modulating the expression of virulence factors. The coordinated inhibition of Rot synthesis by the Agr TCS, as well as the activation of the Sae TCS, is required for maximal toxin expression and production

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