title: Rapid activation of endothelial cells enables Plasmodium falciparum adhesion to platelet-decorated von Willebrand factor strings.
abstract: During Plasmodium falciparum malaria infections, von Willebrand factor (VWF) levels are elevated, postmortem studies show platelets colocalized with sequestered infected erythrocytes (IEs) at brain microvascular sites, whereas in vitro studies have demonstrated platelet-mediated IE adhesion to tumor necrosis factor-activated brain endothelium via a bridging mechanism. This current study demonstrates how all these observations could be linked through a completely novel mechanism whereby IEs adhere via platelet decorated ultra-large VWF strings on activated endothelium. Using an in vitro laminar flow model, we have demonstrated tethering and firm adhesion of IEs to the endothelium specifically at sites of platelet accumulation. We also show that an IE pro-adhesive state, capable of supporting high levels of binding within minutes of induction, can be removed through the action of the VWF protease ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). We propose that this new mechanism contributes to sequestration both independently of and in concert with current adhesion mechanisms.
authors.affiliation: Liverpool School of Tropical Medicine, Liverpool, United Kingdom. d.bridges@liverpool.ac.uk
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Bridges
authors.forename: James
authors.initials: J
authors.lastname: Bunn
authors.forename: Jan A
authors.initials: JA
authors.lastname: van Mourik
authors.forename: Georges
authors.initials: G
authors.lastname: Grau
authors.forename: Roger J S
authors.initials: RJ
authors.lastname: Preston
authors.forename: Malcolm
authors.initials: M
authors.lastname: Molyneux
authors.forename: Valery
authors.initials: V
authors.lastname: Combes
authors.forename: James S
authors.initials: JS
authors.lastname: O'Donnell
authors.forename: Bas
authors.initials: B
authors.lastname: de Laat
authors.forename: Alister
authors.initials: A
authors.lastname: Craig
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000071120:ADAMTS13 Protein; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001792:Blood Platelets / Q000378:metabolism; D018955:CD36 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism / Q000469:parasitology*; D004912:Erythrocytes / Q000166:cytology / Q000378:metabolism / Q000469:parasitology*; D006801:Humans; D016778:Malaria, Falciparum / Q000378:metabolism* / Q000469:parasitology; D010963:Plasmodium falciparum; D014471:Umbilical Veins / Q000166:cytology; D014841:von Willebrand Factor / Q000276:immunology / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D018955:CD36 Antigens; D014841:von Willebrand Factor; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human