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

Abstract 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, allowing phagosomal escape 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 listeriolysin O and various other proteins crucially involved in pathogen-host interactions. Listeria secreting caspase-uncleavable listeriolysin O 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.