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Abstract
Staphylococccus aureus represents one of the most challenging human pathogens as well as a common colonizer of human skin and mucosal surfaces. S. aureus causes a wide range of diseases from skin and soft tissue infection (SSTI) to debilitating and life-threatening conditions such as osteomyelitis, endocarditis, and necrotizing pneumonia. The range of diseases reflects the remarkable diversity of the virulence factors produced by this pathogen, including surface antigens involved in the establishment of infection and a large number of toxins that mediate a vast array of cellular responses. The staphylococcal toxins are generally believed to have evolved to disarm the innate immune system, the first line of defense against this pathogen. This review focuses on recent advances on elucidating the biological functions of S. aureus bicomponent pore-forming toxins (BCPFTs) and their utility as targets for preventive and therapeutic intervention. These toxins are cytolytic to a variety of immune cells, primarily neutrophils, as well as cells with a critical barrier function. The lytic activity of BCPFTs towards immune cells implies a critical role in immune evasion, and a number of epidemiological studies and animal experiments relate these toxins to clinical disease, particularly SSTI and necrotizing pneumonia. Antibody-mediated neutralization of this lytic activity may provide a strategy for development of toxoid-based vaccines or immunotherapeutics for prevention or mitigation of clinical diseases. However, certain BCPFTs have been proposed to act as danger signals that may alert the immune system through an inflammatory response. The utility of a neutralizing vaccination strategy must be weighed against such immune-activating potential.
Highlights
Staphylococcus aureus (S. aureus) is a ubiquitous, formidable Gram-positive microorganism that acts both as a human commensal, as well as a pathogen
(Figure 1C), HlgCB was as potent a leukocidin as Panton Valentine Leukocidin (PVL), as previously reported [62,63,80], but failed to lyse rabbit red blood cells (Figure 1D). These data indicate that the current nomenclature of bicomponent pore-forming toxins (BCPFTs) as leukocidins versus hemolysins inaccurately reflects their breadth of functional activities
The most divergent leukotoxin is LukAB with sequence identity of 33%–40% within each class with other members of BCPFT family. Based on this sequence identity and the breadth of functional activities of these toxins, it is possible that vaccine and immunotherapeutic intervention strategies can be devised that provide broad neutralizing activity. Consistent with this hypothesis we found that antibodies raised against LukS-PV neutralize leukotoxic activity towards human polymorphonuclear cells (PMN) of PVL-negative S. aureus strains (Figure 3A)
Summary
Staphylococcus aureus (S. aureus) is a ubiquitous, formidable Gram-positive microorganism that acts both as a human commensal, as well as a pathogen. In addition to SCCmec IV, a prominent characteristic of these major CA-MRSA clones is that they all have the lukPV operon encoding the Panton Valentine Leukocidin (PVL) [9], carried by the lysogenic phages φSLT, φPVL, φSA2MW and φSA2usa [10,11,12] This observation renewed interest in this pore-forming bicomponent toxin which was first described by Panton and Valentine in 1932 [13]. The bicomponent pore-forming toxins (BCPFTs), consist of two subunits with a beta barrel structure that acquire pore-forming conformation upon binding to specific cellular receptors followed by hetero-oligomerization at the plasma membrane of the target cells. Significant association has been reported between LukED expression and S. aureus invasive disease [54,55]. This is substantially facilitated by recent discovery of several receptors for these toxins
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