title: Ultralarge von Willebrand factor fibers mediate luminal Staphylococcus aureus adhesion to an intact endothelial cell layer under shear stress.
abstract: 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.
  
  
  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.
authors.affiliation: Experimental Dermatology, Department of Dermatology, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.
authors.forename: Karin I
authors.initials: KI
authors.lastname: Pappelbaum
authors.forename: Christian
authors.initials: C
authors.lastname: Gorzelanny
authors.forename: Sandra
authors.initials: S
authors.lastname: Grässle
authors.forename: Jan
authors.initials: J
authors.lastname: Suckau
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Laschke
authors.forename: Markus
authors.initials: M
authors.lastname: Bischoff
authors.forename: Corinne
authors.initials: C
authors.lastname: Bauer
authors.forename: Marina
authors.initials: M
authors.lastname: Schorpp-Kistner
authors.forename: Christopher
authors.initials: C
authors.lastname: Weidenmaier
authors.forename: Reinhard
authors.initials: R
authors.lastname: Schneppenheim
authors.forename: Tobias
authors.initials: T
authors.lastname: Obser
authors.forename: Bhanu
authors.initials: B
authors.lastname: Sinha
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Schneider
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000071120:ADAMTS13 Protein; D000818:Animals; D000925:Anticoagulants / Q000378:metabolism / Q000494:pharmacology; D001422:Bacterial Adhesion / Q000502:physiology; D001792:Blood Platelets / Q000378:metabolism / Q000382:microbiology; D004697:Endocarditis, Bacterial / Q000378:metabolism* / Q000382:microbiology / Q000517:prevention & control; D042783:Endothelial Cells / Q000166:cytology / Q000382:microbiology* / Q000502:physiology; D005340:Fibrinogen / Q000378:metabolism / Q000494:pharmacology; D006493:Heparin / Q000378:metabolism / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010316:Particle Size; D012867:Skin / Q000166:cytology / Q000382:microbiology; D013203:Staphylococcal Infections / Q000378:metabolism* / Q000382:microbiology / Q000517:prevention & control; D013211:Staphylococcus aureus / Q000378:metabolism* / Q000472:pathogenicity; D013314:Stress, Mechanical; D037521:Virulence Factors / Q000378:metabolism; D014841:von Willebrand Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D000925:Anticoagulants; D037521:Virulence Factors; D014841:von Willebrand Factor; D005340:Fibrinogen; D006493:Heparin; D051722:ADAM Proteins; C502939:ADAMTS13 protein, mouse; D008666:Metalloendopeptidases; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human
keywords: blood flow velocity; cardiovascular diseases; endocarditis, bacterial; endothelium; infection; von Willebrand factor