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<p>Proliferation of the emerging zoonotic pathogen <i>Streptococcus equi</i> subsp. <i>zooepidemicus</i> in the meninges is linked to mortality in pigs and morbidity in humans. The mechanisms underlying the remarkable capacity of hypervirulent <i>S.</i> <i>zooepidemicus</i> to proliferate in cerebrospinal fluid (CSF) are largely undefined. Here, using genetically barcoded <i>S.</i> <i>zooepidemicus</i>, we found that following systemic infection of mice, only ~1–10 <i>S.</i> <i>zooepidemicus</i> clones invade the meninges where they subsequently replicate ~10<sup>7</sup>-fold. Subsequent transposon insertion sequencing experiments, plus validation work with bacterial mannose phosphotransferase system (PTS<sub>man</sub>)-defective strains, identified the PTS<sub>man</sub>, which imports glucose, as essential for <i>S.</i> <i>zooepidemicus</i> proliferation in CSF. The <i>S.</i> <i>zooepidemicus</i> PTS<sub>man</sub> promoter confers species-specific constitutive transcription of PTS<sub>man</sub>, enabling glucose acquisition at low glucose concentrations and limiting activation of the stringent response, leading to pathogen replication in CSF. Our findings reveal how the rewiring of PTS<sub>man</sub> in the control of <i>S.</i> <i>zooepidemicus</i> metabolism enables this pathogen to adapt to and replicate in CSF during meningitis.</p>

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Zoonotic Streptococcus imports glucose to inhibit stringent response and promote growth during meningitis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月15日

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  • Chen Yuan,
  • Karthik Hullahalli,
  • Hao Huang,
  • Siqi Zhao,
  • Wenqing Wang,
  • Xingyu Tian,
  • Xin Li,
  • Linya Xia,
  • Yuchang Wang,
  • Fei Pan,
  • Ying Liang,
  • Yurui Xie,
  • Yue Li,
  • Hongjie Fan,
  • Matthew K. Waldor,
  • Zhe Ma

摘要

Proliferation of the emerging zoonotic pathogen Streptococcus equi subsp. zooepidemicus in the meninges is linked to mortality in pigs and morbidity in humans. The mechanisms underlying the remarkable capacity of hypervirulent S. zooepidemicus to proliferate in cerebrospinal fluid (CSF) are largely undefined. Here, using genetically barcoded S. zooepidemicus, we found that following systemic infection of mice, only ~1–10 S. zooepidemicus clones invade the meninges where they subsequently replicate ~107-fold. Subsequent transposon insertion sequencing experiments, plus validation work with bacterial mannose phosphotransferase system (PTSman)-defective strains, identified the PTSman, which imports glucose, as essential for S. zooepidemicus proliferation in CSF. The S. zooepidemicus PTSman promoter confers species-specific constitutive transcription of PTSman, enabling glucose acquisition at low glucose concentrations and limiting activation of the stringent response, leading to pathogen replication in CSF. Our findings reveal how the rewiring of PTSman in the control of S. zooepidemicus metabolism enables this pathogen to adapt to and replicate in CSF during meningitis.