title: Plasmodium falciparum-induced CD36 clustering rapidly strengthens cytoadherence via p130CAS-mediated actin cytoskeletal rearrangement.
abstract: The adhesion of infected red blood cells (IRBCs) to microvascular endothelium is critical in the pathogenesis of severe malaria. Here we used atomic force and confocal microscopy to examine the adhesive forces between IRBCs and human dermal microvascular endothelial cells. Initial contact of the cells generated a mean ± sd adhesion force of 167 ± 208 pN from the formation of single or multiple bonds with CD36. The strength of adhesion increased by 5- to 6-fold within minutes of contact through a signaling pathway initiated by CD36 ligation by live IRBCs, or polystyrene beads coated with anti-CD36 or PpMC-179, a recombinant peptide representing the minimal binding domain of the parasite ligand PfEMP1 to CD36. Engagement of CD36 led to localized phosphorylation of Src family kinases and the adaptor protein p130CAS, resulting in actin recruitment and CD36 clustering by 50-60% of adherent beads. Uninfected red blood cells or IgG-coated beads had no effect. Inhibition of the increase in adhesive strength by the Src family kinase inhibitor PP1 or gene silencing of p130CAS decreased adhesion by 39 ± 12 and 48 ± 20%, respectively, at 10 dyn/cm(2) in a flow chamber assay. Modulation of adhesive strength at PfEMP1-CD36-actin cytoskeleton synapses could be a novel target for antiadhesive therapy.
authors: Department of Microbiology, Immunology, and Infectious Diseases, 3330 Hospital Dr. NW, Calgary, AB, Canada T2N 4N1.
authors: Shevaun P
authors: SP
authors: Davis
authors: Matthias
authors: M
authors: Amrein
authors: Mark R
authors: MR
authors: Gillrie
authors: Kristine
authors: K
authors: Lee
authors: Daniel A
authors: DA
authors: Muruve
authors: May
authors: M
authors: Ho
mesh_terms: D000199:Actins / Q000378:metabolism; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D002450:Cell Communication; D002478:Cells, Cultured; D050719:Crk-Associated Substrate Protein / Q000235:genetics / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism* / Q000469:parasitology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006790:Host-Parasite Interactions; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D018625:Microscopy, Atomic Force; D018613:Microscopy, Confocal; D010766:Phosphorylation; D010963:Plasmodium falciparum / Q000378:metabolism* / Q000502:physiology; D011485:Protein Binding; D015800:Protozoan Proteins / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D059010:Single-Cell Analysis / Q000379:methods; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; D000199:Actins; C493841:BCAR1 protein, human; D018955:CD36 Antigens; D050719:Crk-Associated Substrate Protein; D015800:Protozoan Proteins; D011720:Pyrazoles; D011743:Pyrimidines; C085731:erythrocyte membrane protein 1, Plasmodium falciparum; D049452:Green Fluorescent Proteins; D019061:src-Family Kinases