PMID:26091719

Citation	Spaan, AN, Schiepers, A, de Haas, CJ, van Hooijdonk, DD, Badiou, C, Contamin, H, Vandenesch, F, Lina, G, Gerard, NP, Gerard, C, van Kessel, KP, Henry, T and van Strijp, JA (2015) Differential Interaction of the Staphylococcal Toxins Panton-Valentine Leukocidin and γ-Hemolysin CB with Human C5a Receptors. J. Immunol. 195:1034-43
Abstract	Staphylococcus aureus is well adapted to the human host. Evasion of the host phagocyte response is critical for successful infection. The staphylococcal bicomponent pore-forming toxins Panton-Valentine leukocidin LukSF-PV (PVL) and γ-hemolysin CB (HlgCB) target human phagocytes through interaction with the complement receptors C5aR1 and C5aR2. Currently, the apparent redundancy of both toxins cannot be adequately addressed in experimental models of infection because mice are resistant to PVL and HlgCB. The molecular basis for species specificity of the two toxins in animal models is not completely understood. We show that PVL and HlgCB feature distinct activity toward neutrophils of different mammalian species, where activity of PVL is found to be restricted to fewer species than that of HlgCB. Overexpression of various mammalian C5a receptors in HEK cells confirms that cytotoxicity toward neutrophils is driven by species-specific interactions of the toxins with C5aR1. By taking advantage of the species-specific engagement of the toxins with their receptors, we demonstrate that PVL and HlgCB differentially interact with human C5aR1 and C5aR2. In addition, binding studies illustrate that different parts of the receptor are involved in the initial binding of the toxin and the subsequent formation of lytic pores. These findings allow a better understanding of the molecular mechanism of pore formation. Finally, we show that the toxicity of PVL, but not of HlgCB, is neutralized by various C5aR1 antagonists. This study offers directions for the development of improved preclinical models for infection, as well as for the design of drugs antagonizing leukocidin toxicity.
Links	PubMed PMC4506853 Online version:10.4049/jimmunol.1500604
Keywords	Amino Acid Sequence; Animals; Bacterial Proteins/immunology; Bacterial Toxins/immunology; Cattle; Cell Line; Exotoxins/immunology; HEK293 Cells; Hemolysin Proteins/immunology; Humans; Immune Evasion/immunology; Leukocidins/immunology; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Neutrophils/immunology; Phagocytes/immunology; Protein Binding; Protein Structure, Tertiary; Receptor, Anaphylatoxin C5a/antagonists & inhibitors; Receptor, Anaphylatoxin C5a/immunology; Receptors, Chemokine/antagonists & inhibitors; Receptors, Chemokine/immunology; Staphylococcal Infections/immunology; Staphylococcus aureus/pathogenicity
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
STAAU:B0YLX3		GO:0009405: pathogenesis	ECO:0000314:		P		Figure 1A. Pore formation in freshly isolated neutrophils from different mammalian species after incubation with PVL shows differential species-specific cytotoxicity of PVL. PVL is active only toward human and rabbit neutrophils, but not toward neutrophils from macaque, cow, and mouse	complete CACAO 11182

References

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