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.
Highlights
Staphylococcus aureus is an important human pathogen that can cause serious diseases [1]
The action of Panton-Valentine leukocidin (PVL) appears to be tightly restricted to these species, as neutrophils isolated from Java monkeys (Macaca fascicularis, cynomolgus), the most commonly used non-human primate in biomedical research, were not killed in response to PVL (Figure 1C)
As PVL was found in almost all mutant of strain USA300 WT (MRSA) strains that cause community-associated methicillin-resistant S. aureus (CA-MRSA) infections, such as necrotizing pneumonia, skin- and soft tissue infections, it was assumed to be a crucial virulence factor [4,6]
Summary
Staphylococcus aureus is an important human pathogen that can cause serious diseases [1]. Necrotizing pneumonia seems to be a specific disease entity and often follows infection with influenza virus [4,5]. To combat these life-threatening infections, there is a need to better understand the bacteria-host interaction and virulence factors involved. PVL is a two component pore-forming toxin, which mainly acts on neutrophils [7]. It is expressed by only a small percentage of S. aureus wild-type isolates (2–3%) [8], but it is highly prevalent in S. aureus strains isolated from necrotizing infections [4,6]
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