Ultralarge von Willebrand factor fibers mediate luminal Staphylococcus aureus adhesion to an intact endothelial cell layer under shear stress
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Ultralarge von Willebrand factor fibers mediate luminal Staphylococcus aureus adhesion to an intact endothelial cell layer under shear stress. / Pappelbaum, Karin I; Gorzelanny, Christian; Grässle, Sandra; Suckau, Jan; Laschke, Matthias W; Bischoff, Markus; Bauer, Corinne; Schorpp-Kistner, Marina; Weidenmaier, Christopher; Schneppenheim, Reinhard; Obser, Tobias; Sinha, Bhanu; Schneider, Stefan W.
In: CIRCULATION, Vol. 128, No. 1, 02.07.2013, p. 50-9.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Ultralarge von Willebrand factor fibers mediate luminal Staphylococcus aureus adhesion to an intact endothelial cell layer under shear stress
AU - Pappelbaum, Karin I
AU - Gorzelanny, Christian
AU - Grässle, Sandra
AU - Suckau, Jan
AU - Laschke, Matthias W
AU - Bischoff, Markus
AU - Bauer, Corinne
AU - Schorpp-Kistner, Marina
AU - Weidenmaier, Christopher
AU - Schneppenheim, Reinhard
AU - Obser, Tobias
AU - Sinha, Bhanu
AU - Schneider, Stefan W
PY - 2013/7/2
Y1 - 2013/7/2
N2 - BACKGROUND: During pathogenesis of infective endocarditis, Staphylococcus aureus adherence often occurs without identifiable preexisting heart disease. However, molecular mechanisms mediating initial bacterial adhesion to morphologically intact endocardium are largely unknown.METHODS AND RESULTS: Perfusion of activated human endothelial cells with fluorescent bacteria under high-shear-rate conditions revealed 95% attachment of the S aureus by ultralarge von Willebrand factor (ULVWF). Flow experiments with VWF deletion mutants and heparin indicate a contribution of the A-type domains of VWF to bacterial binding. In this context, analyses of different bacterial deletion mutants suggest the involvement of wall teichoic acid but not of staphylococcal protein A. The presence of inactivated platelets and serum increased significantly ULVWF-mediated bacterial adherence. ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13) caused a dose-dependent reduction of bacterial binding and a reduced length of ULVWF, but single cocci were still tethered by ULVWF at physiological levels of ADAMTS13. To further prove the role of VWF in vivo, we compared wild-type mice with VWF knockout mice. Binding of fluorescent bacteria was followed in tumor necrosis factor-α-stimulated tissue by intravital microscopy applying the dorsal skinfold chamber model. Compared with wild-type mice (n=6), we found less bacteria in postcapillary (60±6 versus 32±5 bacteria) and collecting venules (48±5 versus 18±4 bacteria; P<0.05) of VWF knockout mice (n=5).CONCLUSIONS: Our data provide the first evidence that ULVWF contributes to the initial pathogenic step of S aureus-induced endocarditis in patients with an apparently intact endothelium. An intervention reducing the ULVWF formation with heparin or ADAMTS13 suggests novel therapeutic options to prevent infective endocarditis.
AB - BACKGROUND: During pathogenesis of infective endocarditis, Staphylococcus aureus adherence often occurs without identifiable preexisting heart disease. However, molecular mechanisms mediating initial bacterial adhesion to morphologically intact endocardium are largely unknown.METHODS AND RESULTS: Perfusion of activated human endothelial cells with fluorescent bacteria under high-shear-rate conditions revealed 95% attachment of the S aureus by ultralarge von Willebrand factor (ULVWF). Flow experiments with VWF deletion mutants and heparin indicate a contribution of the A-type domains of VWF to bacterial binding. In this context, analyses of different bacterial deletion mutants suggest the involvement of wall teichoic acid but not of staphylococcal protein A. The presence of inactivated platelets and serum increased significantly ULVWF-mediated bacterial adherence. ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13) caused a dose-dependent reduction of bacterial binding and a reduced length of ULVWF, but single cocci were still tethered by ULVWF at physiological levels of ADAMTS13. To further prove the role of VWF in vivo, we compared wild-type mice with VWF knockout mice. Binding of fluorescent bacteria was followed in tumor necrosis factor-α-stimulated tissue by intravital microscopy applying the dorsal skinfold chamber model. Compared with wild-type mice (n=6), we found less bacteria in postcapillary (60±6 versus 32±5 bacteria) and collecting venules (48±5 versus 18±4 bacteria; P<0.05) of VWF knockout mice (n=5).CONCLUSIONS: Our data provide the first evidence that ULVWF contributes to the initial pathogenic step of S aureus-induced endocarditis in patients with an apparently intact endothelium. An intervention reducing the ULVWF formation with heparin or ADAMTS13 suggests novel therapeutic options to prevent infective endocarditis.
KW - ADAM Proteins
KW - Animals
KW - Anticoagulants
KW - Bacterial Adhesion
KW - Blood Platelets
KW - Endocarditis, Bacterial
KW - Endothelial Cells
KW - Fibrinogen
KW - Heparin
KW - Human Umbilical Vein Endothelial Cells
KW - Humans
KW - Metalloendopeptidases
KW - Mice
KW - Mice, Knockout
KW - Particle Size
KW - Skin
KW - Staphylococcal Infections
KW - Staphylococcus aureus
KW - Stress, Mechanical
KW - Virulence Factors
KW - von Willebrand Factor
U2 - 10.1161/CIRCULATIONAHA.113.002008
DO - 10.1161/CIRCULATIONAHA.113.002008
M3 - SCORING: Journal article
C2 - 23720451
VL - 128
SP - 50
EP - 59
JO - CIRCULATION
JF - CIRCULATION
SN - 0009-7322
IS - 1
ER -