Staphylococcal superantigen-like 5 binds PSGL-1 and inhibits P-selectin-mediated neutrophil rolling.
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 (CHIPS(31-121)), 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 toward 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.
Bestebroer
Jovanka
J
Experimental Microbiology, University Medical Center Utrecht, The Netherlands. J.Bestebroer@umcutrecht.nl
Poppelier
Miriam J J G
MJ
Ulfman
Laurien H
LH
Lenting
Peter J
PJ
Denis
Cecile V
CV
van Kessel
Kok P M
KP
van Strijp
Jos A G
JA
de Haas
Carla J C
CJ
D000818:Animals; D001427:Bacterial Toxins / Q000378:metabolism / Q000633:toxicity; D001483:Base Sequence; D001667:Binding, Competitive; D016466:CHO Cells; D002478:Cells, Cultured; D003001:Cloning, Molecular; D006224:Cricetinae; D003412:Cricetulus; D004269:DNA, Bacterial / Q000235:genetics; D005098:Exotoxins / Q000378:metabolism / Q000633:toxicity; D006801:Humans; D066298:In Vitro Techniques; D036904:Leukocyte Rolling / Q000187:drug effects* / Q000502:physiology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology*; D019007:P-Selectin / Q000378:metabolism*; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism / Q000633:toxicity; D013211:Staphylococcus aureus / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D018089:Superantigens / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity*
D001427:Bacterial Toxins; D004269:DNA, Bacterial; D005098:Exotoxins; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D011994:Recombinant Proteins; D018089:Superantigens