The small β-pore-forming α-toxin, also termed α-hemolysin or Hla is considered to be an important virulence factor of Staphylococcus aureus. Perforation of the plasma membrane (PM) by Hla leads to uncontrolled flux of ions and water. Already a small number of toxin pores seems to be sufficient to induce complex cellular responses, many of which depend on the efflux of potassium. In this article, we discuss the implications of secondary membrane lesions, for example, by endogenous channels, for Hla-mediated toxicity, for calcium-influx and membrane repair. Activation of purinergic receptors has been proposed to be a major contributor to the lytic effects of various pore forming proteins, but new findings raise doubts that this holds true for Hla. However, the recently discovered cellular pore forming proteins gasdermin D and Mixed lineage kinase domain-like pseudokinase (MLKL) which perforate the PM from the cytosolic side might contribute to both calcium-influx-dependent damage and membrane repair. Activation of endogenous pore forming proteins by Hla above a threshold concentration could explain the apparent dependence of pore characteristics on toxin concentrations. If secondary membrane damage in the aftermath of Hla-attack contributes significantly to overall PM permeability, it might be an interesting target for new therapeutic approaches.
Keywords: ADAM10; MLKL; calcium; endocytosis; gasdermin D; pore-forming toxin.