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<p>Intracellular vacuolar pathogens replicate within membrane-bound compartments known as pathogen-containing vacuoles (PCVs). Maintaining the integrity of these vacuoles is essential for creating a permissive niche that supports pathogen survival and proliferation. In this study, we show that <i>Salmonella enterica</i> serovar Typhimurium co-opts the host mitochondrial citrate carrier (CIC) to promote its intracellular replication by detoxifying the <i>Salmonella</i>-containing vacuole (SCV). Loss of CIC significantly impairs <i>Salmonella</i> growth within host cells, as CIC recruitment to SCVs regulates local citrate levels and mitigates the production of reactive oxygen species (ROS), thereby reducing oxidative stress. Mechanistically, we identify the SPI-2 effector SseF as a critical factor that interacts with CIC and the GTPase RAB7, enabling CIC recruitment to the SCV membrane. These findings reveal a previously unrecognized strategy by which an intracellular pathogen hijacks a mitochondrial metabolite transporter to modulate the vacuolar environment and evade host antimicrobial defenses. Notably, pharmacological inhibition of CIC sensitizes <i>Salmonella</i> to host immune pressures, highlighting CIC as a potential target for host-directed antimicrobial therapy.</p>

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Intracellular Salmonella hijacks the mitochondrial citrate carrier to evade host oxidative defenses

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月6日

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  • Chieh-Hua Fu,
  • Yu-Ting Hsu,
  • Shao-Chun Hsu,
  • Nai-Shu Chen,
  • Hsueh-Wen Hu,
  • Ting-Yin Wu,
  • Yi-Jou Huang,
  • Ying-Chu Chen,
  • An-Chi Luo,
  • Yu-Tsung Huang,
  • Shu-Jung Chang

摘要

Intracellular vacuolar pathogens replicate within membrane-bound compartments known as pathogen-containing vacuoles (PCVs). Maintaining the integrity of these vacuoles is essential for creating a permissive niche that supports pathogen survival and proliferation. In this study, we show that Salmonella enterica serovar Typhimurium co-opts the host mitochondrial citrate carrier (CIC) to promote its intracellular replication by detoxifying the Salmonella-containing vacuole (SCV). Loss of CIC significantly impairs Salmonella growth within host cells, as CIC recruitment to SCVs regulates local citrate levels and mitigates the production of reactive oxygen species (ROS), thereby reducing oxidative stress. Mechanistically, we identify the SPI-2 effector SseF as a critical factor that interacts with CIC and the GTPase RAB7, enabling CIC recruitment to the SCV membrane. These findings reveal a previously unrecognized strategy by which an intracellular pathogen hijacks a mitochondrial metabolite transporter to modulate the vacuolar environment and evade host antimicrobial defenses. Notably, pharmacological inhibition of CIC sensitizes Salmonella to host immune pressures, highlighting CIC as a potential target for host-directed antimicrobial therapy.