Figure 3.

PLY is a trigger for multiple cellular responses. PLY interacts with cells and, depending on PLY concentration and the intracellular Ca²⁺ levels, induces a variety of antipodal cellular responses that can lead to irreversible damage or the induction of cellular repair mechanisms. Left Panel: At lytic amounts, the overwhelming increase in intracellular Ca²⁺ levels induces the surface exposure of actin which facilitate Sp adhesion and invasion, increasing cell death. In addition, PLY-mediated microtubule stabilization may perturb axonal transport, likely contributing neuronal damage. Also, in neuronal cells, p38/MAPK activation is detrimental for the host cell as it increases ROS production and induces senescence. High PLY concentrations cause irreversible mitochondrial damage by inducing swelling, loss of mitochondrial membrane potential, and morphologic and metabolic alterations. Concomitantly with Ca ²⁺ overload, mitochondrial permeability increases, the ATP levels decrease, and mitochondrial DNA is released into the cytosol. Following these events, the mitochondrial apoptosis-induced factor (AIF) reaches the cytoplasm and activates caspase-independent cell death. Right Panel: At sub-lytic amounts, the influx of limited amounts of extracellular Ca²⁺ triggers the sequential recruitment of annexins to the damaged sites where they assemble in 3D arrays to clog the PM pore. Increased intracellular Ca²⁺ also induces cytoskeleton remodeling through the activation of small GTPases Rac1 and RhoA and triggers PM rearrangements culminating in PM blebbing and ESCRT-mediated release of microvesicles containing PLY, annexins, actin-binding and Ca²⁺ regulated proteins, ESCRT components and mitochondrial DNA among others. Released microvesicles promote survival by eliminating the pore, transporting danger signals and enhancing immune responses. In response to K⁺ efflux cell survival pathways such p38/MAPK are activated and stimulate the production of pro-inflammatory cytokines such as IL-8, promoting neutrophil recruitment, and enhancing phagosomal integrity, thus limiting the release of toxic bacterial components into the cytosol.