Staphylococcus aureus α-Toxin: Nearly a Century of Intrigue

Staphylococcus aureus secretes a number of host-injurious toxins, among the most prominent of which is the small beta-barrel pore-forming toxin alpha-hemolysin. Initially named based on its properties as a red blood cell lytic toxin, early studies suggested a far greater complexity of alpha-hemolysin action as nucleated cells also exhibited distinct responses to intoxication. The hemolysin, most aptly referred to as alpha-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 alpha-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 alpha-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 alpha-toxin in modulation of the complex interaction of S. aureus with its human host.