Cell targeting by the Staphylococcus aureus pore-forming toxins: it's not just about lipids

•Staphylococcus aureus pore-forming toxins (PFTs) use different proteinaceous receptors to target host cells.•Receptors explain cell-type and species tropisms exhibited by S. aureus toxins.•Human-specific receptors underscore the limitations of animal models in PFT research.

Staphylococcus aureus employs numerous pore-forming cytotoxins to injure host immune cells and promote infection. Until recently, it was unclear how these cytotoxins targeted specific cell types for lysis. Membrane lipids were initially postulated to be cytotoxin receptor candidates. However, the cell-type specificity and species-dependent targeting of these toxins did not support lipids as sole receptors. The recent identification of proteinaceous receptors for several S. aureus cytotoxins now provides an explanation for the observed tropism. These findings also have important implications for the implementation of animal models to study S. aureus pathogenesis, and for the development of novel therapeutics.