Streptococcus pyogenes Malate Degradation Pathway Links pH Regulation and Virulence

<jats:title>ABSTRACT</jats:title> <jats:p> The ability of <jats:named-content content-type="genus-species">Streptococcus pyogenes</jats:named-content> to infect different niches within its human host most likely relies on its ability to utilize alternative carbon sources. In examining this question, we discovered that all sequenced <jats:named-content content-type="genus-species">S. pyogenes</jats:named-content> strains possess the genes for the malic enzyme (ME) pathway, which allows malate to be used as a supplemental carbon source for growth. ME is comprised of four genes in two adjacent operons, with the regulatory two-component MaeKR required for expression of genes encoding a malate permease ( <jats:italic>maeP</jats:italic> ) and malic enzyme ( <jats:italic>maeE</jats:italic> ). Analysis of transcription indicated that expression of <jats:italic>maeP</jats:italic> and <jats:italic>maeE</jats:italic> is induced by both malate and low pH, and induction in response to both cues is dependent on the MaeK sensor kinase. Furthermore, both <jats:italic>maePE</jats:italic> and <jats:italic>maeKR</jats:italic> are repressed by glucose, which occurs via a CcpA-independent mechanism. Additionally, malate utilization requires the PTS transporter EI enzyme (PtsI), as a PtsI <jats:sup>–</jats:sup> mutant fails to express the ME genes and is unable to utilize malate. Virulence of selected ME mutants was assessed in a murine model of soft tissue infection. MaeP <jats:sup>–</jats:sup> , MaeK <jats:sup>–</jats:sup> , and MaeR <jats:sup>–</jats:sup> mutants were attenuated for virulence, whereas a MaeE <jats:sup>–</jats:sup> mutant showed enhanced virulence compared to that of the wild type. Taken together, these data show that ME contributes to <jats:named-content content-type="genus-species">S. pyogenes</jats:named-content> ' carbon source repertory, that malate utilization is a highly regulated process, and that a single regulator controls ME expression in response to diverse signals. Furthermore, malate uptake and utilization contribute to the adaptive pH response, and ME can influence the outcome of infection. </jats:p>