Staphylococcus aureus hemolysins, bi-component leukocidins, and cytolytic peptides: a redundant arsenal of membrane-damaging virulence factors?

Abstract

One key aspect of the virulence of Staphylococcus aureus lies in its ability to target the host cell membrane with a large number of membrane-damaging toxins and peptides. In this review, we describe the hemolysins, the bi-component leukocidins (which include the Panton Valentine leukocidin, LukAB/GH, and LukED), and the cytolytic peptides (phenol soluble modulins). While at first glance, all of these factors might appear redundant, it is now clear that some of these factors play specific roles in certain S. aureus life stages and diseases or target specific cell types or species. In this review, we present an update of the literature on toxin receptors and their cell type and species specificities. Furthermore, we review epidemiological studies and animal models illustrating the role of these membrane-damaging factors in various diseases. Finally, we emphasize the interplay of these factors with the host immune system and highlight all their non-lytic functions.

Keywords: PSM; Panton Valentine leukocidin; Staphylococcus aureus; hemolysin; inflammasome; leukocidin; neutrophil; pore-forming toxin.

Figure 1

Interplay between membrane-damaging (poly)peptides and the innate immune system. (1) In physiological conditions, differences in [Ca²⁺] and [K⁺] are actively maintained between the extracellular space and the cytosol. (2) Insertion of a PFT or membrane damage leads to a direct or indirect rise in [Ca²⁺]_i. (3) Similarly, engagement of FPR2 by PSMα triggers an increase in [Ca²⁺]_i. (4) [Ca²⁺]_i controls NF-κB and (5) cPLA2 activation. (6) TLR2 and 4 might also trigger NF-κB translocation in the nucleus by sensing LukS-PV and LukF-PV. (7) Insertion of a PFT or membrane damage leads to a rapid fall in [K⁺]_i, leading to (8) MAP kinase and (9) NLRP3 inflammasome activation. (10) Ceramide generated by β-hemolysin might also directly activate the NLRP3 inflammasome. (11) In addition, ceramide has been reported to inhibit IL-8 secretion.

Figure 2

Non-lytic functions of hemolysins, bi-component toxins, and PSMs. (1) E-cadherin is important for maintaining tight junctions and epithelial barrier function. α-Hemolysin binds ADAM10 and relocalizes it to E-cadherin-containing microdomains. ADAM10 cleaves E-cadherin, leading to loss in epithelial barrier function. (2) Exposure of the underlying glycosaminoglycans-rich extracellular matrix to LukS-PV signal peptide favors S. aureus adhesion. (3) PSM-mec RNA controls the transcription of virulence factors, including PSMα. (4) β-Hemolysin binds DNA, forming nucleoproteins nucleating S. aureus biofilm. PSMβ acts as surfactant, promoting the formation of intra-biofilm tunnels and bacterial dissemination from biofilms. PSM-mec enhances biofilm formation (5) In addition, PSMs have antibacterial activity, which may be relevant in lysing competing colonizing bacteria. (6) Finally, PSMs in synergy with β-hemolysin participate in phagosome lysis and escape into the host cytosol.