Cellular Responses to Bacterial Pore-Forming Toxins

Pore-forming toxins (PFTs) represent the largest class of bacterial protein toxins and constitute major virulence factors produced by pathogenic bacteria during infection. Pore formation appears to be an ancient form of attack, which is also found in hydrozoans, plants and humans. Bacteria secrete PFTs in the medium as water-soluble monomeric proteins that diffuse and bind to target cells via specific receptors. After binding, monomers undergo multimerization and insertion into the plasma membrane, which leads to the formation of a hydrophilic transmembrane channel. Consequences of PFT pores are loss of membrane potential, disruption of ion gradients and changes in cytosolic ion composition. Cells have evolved different response to PFT injury through the activation of various signalling pathways. Two types of PFTs are used in this study – aerolysin produced by Aeromonas hydrophila and listeriolysin-O produced by Listeria monocytogenes – that form small and large pores, respectively. We show that changes in cellular ion composition are the initial event sensed by the cells. In particular, changes in potassium levels lead to the activation of different signalling pathways some of which promote cell survival. Depending on the extent and the duration of intoxication, these pathways can lead to the recovery of membrane integrity and contribute to restore ions homeostasis. Interestingly, this recovery process is independent on protein synthesis but requires the activation of the pre-existing mitogen-activated protein kinases (MAPK) p38 and ERK. In addition to these pathways, cells enter an energy saving state by inducing arrest in protein synthesis, activation of the autophagy recycling machinery and accumulation of cellular lipid droplets. Taken together, the results presented in this study raise the notion that upon membrane disruption, cells activate a large variety of signalling pathways. These pathways are similarly induced by small and large PFTs, whereas the specific involvement in the recovery process depends on the type of PFT. This suggests that the differences observed in recovery kinetics among the PFTs depend on the capacity of the cell the cope with different types of pores, more than on the type of pathway induced by intoxication.