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.

Safety and immunogenicity of a recombinant Staphylococcus aureus α-toxoid and a recombinant Panton-Valentine leukocidin subunit, in healthy adults

“…[20][21][22] a-toxin is a highly conserved toxin that causes tissue barrier disruption at host interfaces lined by epithelial or endothelial cells, and undermines the host immune response. 23 Reduced skin lesion size and dermonecrosis were observed in mice immunized with a nontoxigenic form of a-toxin, following infection with USA300. 24 In observational studies, higher levels of IgG antibody to a-toxin have been associated with reduced risk of sepsis in adult patients with invasive staphylococcal infections.…”

The adherens junctions control susceptibility to Staphylococcus aureus α-toxin

“…Originally described solely for its ability to induce lysis of erythrocytes, it is now appreciated that α-toxin exerts pleiotropic effects on a diverse set of host cells (13). In addition to inducing cell death, at sublytic concentrations α-toxin has been described to alter a wide variety of cellular processes, including cell signaling, proliferation, immunomodulation, autophagy, and others (13)(14)(15)(16)(17).…”

“…After secretion as a soluble monomer, α-toxin oligomerizes on the targeted host cell surface via interactions with its high-affinity metalloprotease receptor, a disintegrin and metalloprotease 10 (ADAM10), forming a 1-3-nm pore that spans the cellular membrane lipid bilayer (11,12). Originally described solely for its ability to induce lysis of erythrocytes, it is now appreciated that α-toxin exerts pleiotropic effects on a diverse set of host cells (13). In addition to inducing cell death, at sublytic concentrations α-toxin has been described to alter a wide variety of cellular processes, including cell signaling, proliferation, immunomodulation, autophagy, and others (13)(14)(15)(16)(17).…”

Inhibition of LTA4H expression promotes Staphylococcus aureus elimination by planarians

“…In addition, whether the regeneration process failed or is affected by the knock down of LTA4H should be examined to explain the role of LTA4H in bacterial elimination by planarians. However, we cannot exclude a contribution of the α-toxin produced by S. aureus [12] in our observation. It will be interesting to see if other strains of S. aureus which do not produce α-toxin, such as the S. aureus RN4220 strain, have the same effect on Smed-LTA4H expression, and the effect of the silencing of Smed-LTA4H on S. aureus RN4220 behaviors.…”