Staphylococcus aureus α-toxin: nearly a century of intrigue

Abstract

Staphylococcus aureus secretes a number of host-injurious toxins, among the most prominent of which is the small β-barrel pore-forming toxin α-hemolysin. Initially named based on its properties as a red blood cell lytic toxin, early studies suggested a far greater complexity of α-hemolysin action as nucleated cells also exhibited distinct responses to intoxication. The hemolysin, most aptly referred to as α-toxin based on its broad range of cellular specificity, has long been recognized as an important cause of injury in the context of both skin necrosis and lethal infection. The recent identification of ADAM10 as a cellular receptor for α-toxin has provided keen insight on the biology of toxin action during disease pathogenesis, demonstrating the molecular mechanisms by which the toxin causes tissue barrier disruption at host interfaces lined by epithelial or endothelial cells. This review highlights both the historical studies that laid the groundwork for nearly a century of research on α-toxin and key findings on the structural and functional biology of the toxin, in addition to discussing emerging observations that have significantly expanded our understanding of this toxin in S. aureus disease. The identification of ADAM10 as a proteinaceous receptor for the toxin not only provides a greater appreciation of truths uncovered by many historic studies, but now affords the opportunity to more extensively probe and understand the role of α-toxin in modulation of the complex interaction of S. aureus with its human host.

Figure 1

Structure of α-toxin. Crystal structure of α-toxin derived from the RCSB Protein Data Bank (PDB, 7AHL) and prepared using PYMOL, noting the regions of the toxin that demarcate the entry of the pore (Cap), the membrane-interfacing region (Rim), and the membrane perforating stem.

Figure 2

Cellular responses to intoxication by Hla. Multiple cell types are targeted by α-toxin, each displaying unique effects that are dependent on the relative concentration of toxin to which the cell is exposed.

Figure 3

Dual mechanism of action of α-toxin on susceptible host cells. Model illustrating key functions of the α-toxin (red)-ADAM10 (blue) complex, facilitating membrane binding of the toxin with subsequent oligomerization and pore formation. The formation of the toxin pore leads to two functionally linked outcomes—induction of host cell signaling and/or cellular lysis (dependent on toxin concentration) and the rapid upregulation of the metalloprotease activity of ADAM10 (denoted by a star). ADAM10, in turn, acts in a cell-specific manner to cleave ectodomain-containing proteins (orange) that appear to represent important biological mediators of α-toxin action.