Staphylococcus aureus pore-forming toxins: The interface of pathogen and host complexity

Abstract

Staphylococcus aureus is a prominent human pathogen capable of infecting a variety of host species and tissue sites. This versatility stems from the pathogen's ability to secrete diverse host-damaging virulence factors. Among these factors, the S. aureus pore-forming toxins (PFTs) α-toxin and the bicomponent leukocidins, have garnered much attention for their ability to lyse cells at low concentrations and modulate disease severity. Although many of these toxins were discovered nearly a century ago, their host cell specificities have only been elucidated over the past five to six years, starting with the discovery of the eukaryotic receptor for α-toxin and rapidly followed by identification of the leukocidin receptors. The identification of these receptors has revealed the species- and cell type-specificity of toxin binding, and provided insight into non-lytic effects of PFT intoxication that contribute to disease pathogenesis.

Keywords: Alpha-toxin; Hemolysin; Leukocidin; Pore-forming toxins; S. aureus vaccines and therapeutics; Staphylococcus aureus.

Figure 1. Model of pore-formation mechanism for S. aureus PFTs

(A) α-toxin is secreted as a water-soluble monomer (1), which binds to its receptor ADAM10 (2). The toxin then oligomerizes into a heptamer on the plasma membrane to form the pre-pore (3). Caveolin-1 is thought to interact with Hla within the membrane bilayer to stabilize the prepore. The stem domain is then inserted into the membrane form the β-barrel transmembrane channel (4). (B) The bicomponent leukocidins are also secreted as water-soluble monomers (with the exception of LukAB) (1). The S-component binds the cell surface receptor (2), then recruits the F-component to form heterodimers (3). These dimers oligomerize on the plasma membrane into a hetero-octamer pre-pore (4) prior to transmembrane channel formation (5).

Figure 2. Cellular targets of S. aureus PFTs in humans

(A) Receptor targets of Hla and the bicomponent leukocidins. (B) Human cells currently known to be susceptible to S. aureus PFTs depicting their expressed receptors. Some cell types, namely monocytes and neutrophils, are susceptible to multiple PFTs, whereas others, such as endothelial and epithelial cells, are currently known to only be sensitive to one toxin, Hla.