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

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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 aureus can cause serious diseases, including necrotizing pneumonia, which often affects young immunocompetent patients and has a high lethality rate. Several clinical studies demonstrated a clear association between this form of pneumonia and S. aureus strains carrying the gene for the pore-forming toxin Panton-Valentine leukocidin (PVL). However, laboratory work, which mainly used murine disease models, has created very contrasting results and often fails to show a pathogenic role for PVL. In this study, we demonstrate that the expression of PVL by staphylococcal strains confers strong and rapid cytotoxic activity against neutrophils. However, this action was basically restricted to human cells and could not be reproduced in murine or Java monkeys’ cells. These results indicate that infection-models in mice and in non-human primates fail to replicate the pathogenic activity of PVL seen in human cells. Our data with human neutrophils clearly show that PVL has a major cytotoxic effect, as 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. These results have important implications especially for infections with CA-MRSA strains, which often carry the gene for PVL and have spread widely in the community.