Submitted June 6, 2006
Accepted November 14, 2006
Staphylococcal superantigen-like 5 binds PSGL-1 and inhibits P-selectin-mediated neutrophil rolling
Jovanka Bestebroer*, Miriam J. J. G. Poppelier, Laurien H. Ulfman, Peter J. Lenting, Cecile V. Denis, Kok P.M. van Kessel, Jos A. G. van Strijp, and Carla J. C. de Haas
Experimental Microbiology, University Medical Center Utrecht, Utrecht, Netherlands
Dept of Pulmonary Diseases, University Medical Center Utrecht, Utrecht, Netherlands
Dept of Haematology, University Medical Center Utrecht, Utrecht, Netherlands
INSERM U770, and Faculte de Medecine Paris-Sud, Le Kremlin-Bicetre, France
* Corresponding author; email: j.bestebroer{at}umcutrecht.nl.
Staphylococcus aureus secretes several virulence factors interfering with host-cell functions. Staphylococcal superantigen-like (SSL) proteins are a family of 11 exotoxins with structural homology to superantigens, but with generally unknown functions. Recently, we described that Chemotaxis Inhibitory Protein of Staphylococcus aureus (CHIPS31-121), a potent inhibitor of C5a-induced responses, is structurally homologous to the C-terminal domain of SSL5. Here, we identify P-selectin glycoprotein ligand-1 (PSGL-1), involved in the initial rolling of neutrophils along the endothelium, as a target for SSL5. SSL5 specifically bound to Chinese hamster ovary cells stably expressing PSGL-1 (CHO-PSGL-1), which was dependent of sulfation and sialylation. Furthermore, SSL5 bound to PSGL-1/Ig fusion protein immobilized on a biosensor chip. SSL5 affected binding of soluble P-selectin/Fc chimera, the principle ligand of PSGL-1, to CHO-PSGL-1 cells and inhibited adhesion of neutrophils to immobilized P-selectin under static conditions. Under flow conditions SSL5 strongly decreased neutrophil rolling on immobilized P-selectin/Fc and activated human endothelial cells. In conclusion, SSL5 interferes with the interaction between PSGL-1 and P-selectin, suggesting that S. aureus uses SSL5 to prevent neutrophil extravasation towards the site of infection. This makes SSL5 a potential lead for the development of new anti-inflammatory compounds for disorders characterized by excessive recruitment of leukocytes.
