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Differential Interaction of the Staphylococcal Toxins Panton-Valentine Leukocidin and γ-Hemolysin CB with Human C5a Receptors.

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.
AuthorsAndrás N Spaan, Ariën Schiepers, Carla J C de Haas, Davy D J J van Hooijdonk, Cédric Badiou, Hugues Contamin, François Vandenesch, Gérard Lina, Norma P Gerard, Craig Gerard, Kok P M van Kessel, Thomas Henry, Jos A G van Strijp
JournalJournal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 195 Issue 3 Pg. 1034-43 (Aug 01 2015) ISSN: 1550-6606 [Electronic] United States
PMID26091719 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 by The American Association of Immunologists, Inc.
Chemical References
  • Bacterial Proteins
  • Bacterial Toxins
  • C5AR1 protein, human
  • C5aR2 protein, human
  • Exotoxins
  • Hemolysin Proteins
  • Leukocidins
  • Panton-Valentine leukocidin
  • Receptor, Anaphylatoxin C5a
  • Receptors, Chemokine
  • gamma-hemolysin, Staphylococcus aureus
Topics
  • 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, immunology)
  • Receptors, Chemokine (antagonists & inhibitors, immunology)
  • Staphylococcal Infections (immunology)
  • Staphylococcus aureus (pathogenicity)

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