Staphylococcus aureus Panton-Valentine Leukocidin Is a Very Potent Cytotoxic Factor for Human Neutrophils

Abstract

The role of the pore-forming Staphylococcus aureus toxin Panton-Valentine leukocidin (PVL) in severe necrotizing diseases is debated due to conflicting data from epidemiological studies of community-associated methicillin-resistant S. aureus (CA-MRSA) infections and various murine disease-models. In this study, we used neutrophils isolated from different species to evaluate the cytotoxic effect of PVL in comparison to other staphylococcal cytolytic components. Furthermore, to study the impact of PVL we expressed it heterologously in a non-virulent staphylococcal species and examined pvl-positive and pvl-negative clinical isolates as well as the strain USA300 and its pvl-negative mutant. We demonstrate that PVL induces rapid activation and cell death in human and rabbit neutrophils, but not in murine or simian cells. By contrast, the phenol-soluble modulins (PSMs), a newly identified group of cytolytic staphylococcal components, lack species-specificity. In general, after phagocytosis of bacteria different pvl-positive and pvl-negative staphylococcal strains, expressing a variety of other virulence factors (such as surface proteins), induced cell death in neutrophils, which is most likely associated with the physiological clearing function of these cells. However, the release of PVL by staphylococcal strains caused rapid and premature cell death, which is different from the physiological (and programmed) cell death of neutrophils following phagocytosis and degradation of virulent bacteria. Taken together, our results question the value of infection-models in mice and non-human primates to elucidate the impact of PVL. Our data clearly demonstrate that PVL acts differentially on neutrophils of various species and suggests that PVL has an important cytotoxic role in human neutrophils, which has major implications for the pathogenesis of CA-MRSA infections.

Staphylococcus aureusLukAB cytotoxin kills human neutrophils by targeting the CD11b subunit of the integrin Mac-1

“…A possible explanation is that LukAB may cause disease in the mouse through receptor-independent immunomodulatory mechanisms, as has been as shown for PVL. Similar to LukAB, PVL also displays cytolytic tropism toward human PMNs (16), but has been shown to elicit proinflammatory responses in human PMNs and macrophages (26,27) as well as murine PMNs and macrophages (35,36). These findings suggest that the roles of LukAB and PVL in the mouse may be better explained by immunomodulatory functions rather than cytolytic functions, and indicate that mouse models underestimate the true contribution of these toxins to S. aureus pathobiology in humans.…”

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

“…43 However, the species-specific interaction between toxins and complement receptors have called into question the applicability of mouse models for evaluating potential virulence factors as vaccine targets. 44,45 Despite these limitations, PVL could play a role as a target for active and passive immunization, due to the structural homology of subunits among members of the bi-component cytotoxin family. 46 This structural homology allows for cross-neutralization of several virulence factors with antibodies generated against a single virulence factor.…”

TLR 2 and CD14 Mediate Innate Immunity and Lung Inflammation to Staphylococcal Panton–Valentine Leukocidin In Vivo

“…Previous studies show that human and rabbit neutrophils are highly sensitive to the poreforming properties of PVL and rapidly undergo cell death (11,12). It is generally accepted that myeloid cells are the prime target of PVL and that low concentrations of the toxin cause apoptosis, whereas higher amounts induce lysis of neutrophils (13).…”