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Streptococcus pyogenes Malate Degradation Pathway Links pH Regulation and Virulence

机译：化脓性链球菌苹果酸降解途径与pH调节和毒力有关

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The ability of Streptococcus pyogenes 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 S. pyogenes 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 (maeP) and malic enzyme (maeE). Analysis of transcription indicated that expression of maeP and maeE is induced by both malate and low pH, and induction in response to both cues is dependent on the MaeK sensor kinase. Furthermore, both maePE and maeKR are repressed by glucose, which occurs via a CcpA-independent mechanism. Additionally, malate utilization requires the PTS transporter EI enzyme (PtsI), as a PtsI– 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–, MaeK–, and MaeR– mutants were attenuated for virulence, whereas a MaeE– mutant showed enhanced virulence compared to that of the wild type. Taken together, these data show that ME contributes to S. pyogenes' 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.
机译：化脓性链球菌感染人宿主内不同壁ni的能力最可能取决于其利用替代碳源的能力。在研究此问题时，我们发现所有测序的化脓性链球菌菌株均具有苹果酸酶（ME）途径的基因，这使得苹果酸可用作生长的补充碳源。 ME由两个相邻操纵子中的四个基因组成，表达苹果酸通透酶（ maeP ）和苹果酸酶（ maeE ）的基因表达需要调节性的两成分MaeKR 。转录分析表明， maeP 和 maeE 的表达均受苹果酸和低pH诱导，而对这两种信号的响应诱导均依赖于MaeK传感器激酶。此外， maePE 和 maeKR 均被葡萄糖抑制，这是通过CcpA独立机制发生的。此外，苹果酸的利用需要PTS转运蛋白EI酶（PtsI），因为PtsI – 突变体无法表达ME基因，因此无法利用苹果酸。在软组织感染的鼠模型中评估了选定的ME突变体的毒力。 MaeP – ，MaeK – 和MaeR – 突变体的毒力减弱，而MaeE – 突变体显示增强与野生型相比，毒力更高。综上所述，这些数据表明ME有助于化脓性链球菌的碳源库，苹果酸的利用是一个高度调节的过程，并且单个调节剂响应各种信号控制ME的表达。此外，苹果酸的吸收和利用有助于适应性pH反应，而ME可以影响感染的结果。

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