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<p>Cell death mediated by executioner caspases is essential during organ development and for organismal homeostasis. The mechanistic role of activated executioner caspases in antibacterial defense during infections with intracellular bacteria, such as <i>Listeria monocytogenes</i>, remains elusive. Cell death upon intracellular bacterial infections is considered altruistic to deprive the pathogens of their protective niche. To establish infections in a human host, <i>Listeria monocytogenes</i> deploy virulence mediators, including membranolytic listeriolysin O (LLO) and the invasion associated protein p60 (Iap), allowing phagosomal escape, intracellular replication and cell-to-cell spread. Here, by means of chemical and genetical modifications, we show that the executioner caspases-3 and -7 efficiently inhibit growth of intracellular <i>Listeria monocytogenes</i> in host cells. Comprehensive proteomics revealed multiple caspase-3 substrates in the <i>Listeria</i> secretome, including LLO, Iap and various other proteins crucially involved in pathogen-host interactions. <i>Listeria</i> secreting caspase-uncleavable LLO or Iap gained significant growth advantage in epithelial cells. With that, we uncovered an underappreciated defense barrier and a non-canonical role of executioner caspases to degrade virulence mediators, thus impairing intracellular <i>Listeria</i> growth.</p>

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Executioner caspases degrade essential mediators of pathogen-host interactions to inhibit growth of intracellular Listeria monocytogenes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月30日

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  • Marilyne Lavergne,
  • Raffael Schaerer,
  • Sara De Grandis,
  • Safaa Bouheraoua,
  • Oluwadamilola Adenuga,
  • Tanja Muralt,
  • Tiffany Schaerer,
  • Léa Chèvre,
  • Alessandro Failla,
  • Patricia Matthey,
  • Michael Stumpe,
  • Dieter Kressler,
  • Pierre-Yves Mantel,
  • Michael Walch

摘要

Cell death mediated by executioner caspases is essential during organ development and for organismal homeostasis. The mechanistic role of activated executioner caspases in antibacterial defense during infections with intracellular bacteria, such as Listeria monocytogenes, remains elusive. Cell death upon intracellular bacterial infections is considered altruistic to deprive the pathogens of their protective niche. To establish infections in a human host, Listeria monocytogenes deploy virulence mediators, including membranolytic listeriolysin O (LLO) and the invasion associated protein p60 (Iap), allowing phagosomal escape, intracellular replication and cell-to-cell spread. Here, by means of chemical and genetical modifications, we show that the executioner caspases-3 and -7 efficiently inhibit growth of intracellular Listeria monocytogenes in host cells. Comprehensive proteomics revealed multiple caspase-3 substrates in the Listeria secretome, including LLO, Iap and various other proteins crucially involved in pathogen-host interactions. Listeria secreting caspase-uncleavable LLO or Iap gained significant growth advantage in epithelial cells. With that, we uncovered an underappreciated defense barrier and a non-canonical role of executioner caspases to degrade virulence mediators, thus impairing intracellular Listeria growth.