Responds to the Central Metabolite Pyruvate To Regulate Virulence.

is a versatile bacterial pathogen that can cause significant disease burden and mortality. Like other pathogens, must adapt to its environment to produce virulence factors to survive the immune responses evoked by infection. Despite the importance of environmental signals for 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 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 (CA-MRSA) clone USA300. Specifically, we show that an efficient "pyruvate response" requires the activation of 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 virulon through intricate regulatory networks. Delineation of the influence of host-derived small molecules on the makeup of human pathogens is a growing field in understanding host-pathogen interactions. is a prominent pathogen that colonizes up to one-third of the human population and can cause serious infections that result in mortality in ~15% of cases. Here, we show that pyruvate, a key nutrient and central metabolite, causes global changes to the metabolic flux of and activates regulatory networks that allow significant increases in the production of leucocidins. These and other virulence factors are critical for to infect diverse host niches, initiate infections, and effectively subvert host immune responses. Understanding how environmental signals, particularly ones that are essential to and prominent in the human host, affect virulence will allow us to better understand pathogenicity and consider more-targeted approaches to tackling the current epidemic.