The Staphylococcal Toxin Panton-Valentine Leukocidin Targets Human C5a Receptors

• Staphylococcal Panton-Valentine leukocidin (PVL) targets complement receptors C5aR and C5L2
• The C5aR is the major PVL receptor
• The PVL component LukS-PV is a potent inhibitor of C5a-induced immune cell activation
• C5aR expression levels and interspecies variations determine PVL target specificity

SummaryPanton-Valentine Leukocidin (PVL) is a staphylococcal bicomponent pore-forming toxin linked to severe invasive infections. Target-cell and species specificity of PVL are poorly understood, and the mechanism of action of this toxin in Staphylococcus aureus virulence is controversial. Here, we identify the human complement receptors C5aR and C5L2 as host targets of PVL, mediating both toxin binding and cytotoxicity. Expression and interspecies variations of the C5aR determine cell and species specificity of PVL. The C5aR binding PVL component, LukS-PV, is a potent inhibitor of C5a-induced immune cell activation. These findings provide insight into leukocidin function and staphylococcal virulence and offer directions for future investigations into individual susceptibility to severe staphylococcal disease.