Alteration of epithelial cell lysosomal integrity induced by bacterial cholesterol-dependent cytolysins

Abstract

Bacterial pathogens can interfere during infection with host cell organelles, such as mitochondria, the endoplasmic reticulum‐Golgi system or nuclei. As important cellular functions are often compartmentalized in these organelles, their targeting allows pathogens to manipulate key host functions during infection. Here, we identify lysosomes as a new class of organelles targeted by the pathogenic bacterium Listeria monocytogenes. We demonstrate that extracellular Listeria, via secretion of the pore‐forming toxin listeriolysin O, alters lysosomal integrity in epithelial cells but not in macrophages. Listeriolysin O induces lysosomal membrane permeabilization and release of lysosomal content, such as cathepsins proteases, which remain transiently active in the host cytosol. We furthermore show that other bacterial pore‐forming toxins, such as perfringolysin O and pneumolysin, also induce lysosomes alteration. Together, our data unveil a novel activity of bacterial cholesterol‐dependent cytolysins.

Promyelocytic Leukemia Protein (PML) ControlsListeria monocytogenesInfection

“…The strains used in this study were Listeria monocytogenes strain EGD (BUG 600), an L. monocytogenes EGD Δ hly mutant (BUG 3650 [58]), L. monocytogenes EGDe.PrfA* (BUG 3057), and Salmonella Typhimurium strain SR-11 (BUG 3044; kind gift of F. Norel and V. Robbe-Saule, Institut Pasteur, Paris, France). Listeria strains were grown in brain heart infusion (BHI) broth or agar plates (BD Difco), whereas Salmonella Typhimurium was grown in Luria-Bertani (LB) broth or agar plates (BD Difco).…”

The Lysosomal Membrane Protein Lamp2 Alleviates Lysosomal Cell Death by Promoting Autophagic Flux in Ischemic Cardiomyocytes

“…LCD is characterized by lysosomal membrane permeabilization (LMP) and mediated by the release of lysosomal cathepsins into the cytoplasm, which causes caspase-dependent and caspase-independent cell death (Windelborn and Lipton, 2008;Jiang et al, 2016;Clerc et al, 2018). To date, many pathogenic factors that induce LMP have been discovered, including ROS, lysosomotropic drugs, bacterial and viral products (de Duve, 2005;Huang et al, 2017;Malet et al, 2017). Studies regarding LMP in neuronal ischemic injury have revealed that ROS generation, calcium overload and calpain activation account for the induction of LMP and consequent neuronal death (Yamashima and Oikawa, 2009;Lipton, 2013).…”

How the Study of Listeria Monocytogenes has Led to New Concepts in Biology

“…It was recently shown that the secreted pore-forming toxin LLO induces LMP and the release of cathepsins in the host cytosol via its pore-forming activity [90]. Other cholesterol-dependent cytolysins, such as perfringolysin O and pneumolysin, secreted by other extracellular pathogenic bacteria, also induce LMP [90]. These findings unveil a novel activity of bacterial cholesterol-dependent cytolysins that may interfere with important host cellular pathways linked to lysosomal functions.…”

“…Different stress conditions may alter the integrity of lysosomal membranes (a process known as lysosomal membrane permeabilisation (LMP)), resulting in the leakage of lysosomal content to the cytosol. It was recently shown that the secreted pore-forming toxin LLO induces LMP and the release of cathepsins in the host cytosol via its pore-forming activity [90]. Other cholesterol-dependent cytolysins, such as perfringolysin O and pneumolysin, secreted by other extracellular pathogenic bacteria, also induce LMP [90].…”