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<p><i>Streptococcus suis</i> serotype 2 (SS2) is a prominent pathogen that impacts swine and presents a zoonotic threat to humans; it is a cause of bacterial meningitis, a severe condition linked to neurological impairment and elevated mortality rates. For SS2 to access the central nervous system, it must traverse the blood–brain barrier (BBB); however, the precise mechanisms underlying this process remain incompletely elucidated. In this study, we demonstrate that the RTX family exoprotein A (RfeA), which is secreted by SS2, can be internalized by human brain microvascular endothelial cells (hBMECs) via a caveolae/lipid raft-dependent pathway. RfeA subsequently induces pyroptosis through the NLRP3/Caspase-1 pathway, a process attributed to the increase in mitochondrial reactive oxygen species (mtROS). The interaction between the N-terminus of RfeA and voltage-dependent anion channel 1 (VDAC1) leads to mtROS production, which can be suppressed by a VDAC1 oligomerization inhibitor. RfeA-induced pyroptosis results in disruption of the BBB in both the hBMEC monolayer model and the mouse infection model, thereby promoting bacterial infection of the brain. These findings elucidate a novel mechanism by which SS2 induces pyroptosis to breach the BBB, suggesting a potential target for the prevention and treatment of SS2 infection.</p>

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RfeA from Streptococcus suis serotype 2 triggers NLRP3/Caspase-1-dependent pyroptosis leading to blood–brain barrier disruption

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月25日

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  • Shuai Gao,
  • Wentao Wu,
  • Xingxing Xiao,
  • Jun Li,
  • Sheng Lei,
  • Luying Wang,
  • Xu Han,
  • Yongliang Lou

摘要

Streptococcus suis serotype 2 (SS2) is a prominent pathogen that impacts swine and presents a zoonotic threat to humans; it is a cause of bacterial meningitis, a severe condition linked to neurological impairment and elevated mortality rates. For SS2 to access the central nervous system, it must traverse the blood–brain barrier (BBB); however, the precise mechanisms underlying this process remain incompletely elucidated. In this study, we demonstrate that the RTX family exoprotein A (RfeA), which is secreted by SS2, can be internalized by human brain microvascular endothelial cells (hBMECs) via a caveolae/lipid raft-dependent pathway. RfeA subsequently induces pyroptosis through the NLRP3/Caspase-1 pathway, a process attributed to the increase in mitochondrial reactive oxygen species (mtROS). The interaction between the N-terminus of RfeA and voltage-dependent anion channel 1 (VDAC1) leads to mtROS production, which can be suppressed by a VDAC1 oligomerization inhibitor. RfeA-induced pyroptosis results in disruption of the BBB in both the hBMEC monolayer model and the mouse infection model, thereby promoting bacterial infection of the brain. These findings elucidate a novel mechanism by which SS2 induces pyroptosis to breach the BBB, suggesting a potential target for the prevention and treatment of SS2 infection.