title: CD36 recruits α₅β₁ integrin to promote cytoadherence of P. falciparum-infected erythrocytes.
abstract: The adhesion of Plasmodium falciparum-infected erythrocytes (IRBC) to receptors on different host cells plays a divergent yet critical role in determining the progression and outcome of the infection. Based on our ex vivo studies with clinical parasite isolates from adult Thai patients, we have previously proposed a paradigm for IRBC cytoadherence under physiological shear stress that consists of a recruitment cascade mediated largely by P-selectin, ICAM-1 and CD36 on primary human dermal microvascular endothelium (HDMEC). In addition, we detected post-adhesion signaling events involving Src family kinases and the adaptor protein p130CAS in endothelial cells that lead to CD36 clustering and cytoskeletal rearrangement which enhance the magnitude of the adhesive strength, allowing adherent IRBC to withstand shear stress of up to 20 dynes/cm². In this study, we addressed whether CD36 supports IRBC adhesion as part of an assembly of membrane receptors. Using a combination of flow chamber assay, atomic force and confocal microscopy, we showed for the first time by loss- and gain-of function assays that in the resting state, the integrin α₅β₁ does not support adhesive interactions between IRBC and HDMEC. Upon IRBC adhesion to CD36, the integrin is recruited either passively as part of a molecular complex with CD36, or actively to the site of IRBC attachment through phosphorylation of Src family kinases, a process that is Ca²⁺-dependent. Clustering of β1 integrin is associated with an increase in IRBC recruitment as well as in adhesive strength after attachment (∼40% in both cases). The adhesion of IRBC to a multimolecular complex on the surface of endothelial cells could be of critical importance in enabling adherent IRBC to withstand the high shear stress in the microcirculations. Targeting integrins may provide a novel approach to decrease IRBC cytoadherence to microvascular endothelium.
authors.affiliation: Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Shevaun P
authors.initials: SP
authors.lastname: Davis
authors.forename: Kristine
authors.initials: K
authors.lastname: Lee
authors.forename: Mark R
authors.initials: MR
authors.lastname: Gillrie
authors.forename: Lina
authors.initials: L
authors.lastname: Roa
authors.forename: Matthias
authors.initials: M
authors.lastname: Amrein
authors.forename: May
authors.initials: M
authors.lastname: Ho
mesh_terms: D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D004912:Erythrocytes / Q000378:metabolism* / Q000469:parasitology / Q000473:pathology; D005260:Female; D006801:Humans; D039081:Integrin alpha5beta1 / Q000235:genetics / Q000378:metabolism*; D016778:Malaria, Falciparum / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D010963:Plasmodium falciparum / Q000235:genetics / Q000378:metabolism*; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D018955:CD36 Antigens; D039081:Integrin alpha5beta1; D046912:Multiprotein Complexes; D019061:src-Family Kinases; D002118:Calcium