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.
Highlights
Cell-cell interaction in the microvasculature is a complex process that involves multiple ligands and receptors that mediate different types of adhesive behavior in a sequential manner
Based on our findings with clinical parasite isolates obtained directly from infected patients, we have previously proposed a paradigm for infected red blood cells (IRBC) cytoadherence under flow conditions that consists of a recruitment component that involves tethering, rolling and adhesion of IRBC that is mediated largely by P-selectin, ICAM-1 and CD36 respectively on primary human dermal microvascular endothelium (HDMEC) [3,4]
We showed for the first time a functional association between CD36, a well studied adhesion molecule for parasite adhesion, and a5b1, a member of the integrin family of adhesion molecules that are important for adhesion of leukocytes to blood vessels and cell adhesion to the extracellular matrix
Summary
Cell-cell interaction in the microvasculature is a complex process that involves multiple ligands and receptors that mediate different types of adhesive behavior in a sequential manner. The strength of the interaction between ligands and receptors at each stage of the cascade can be qualitatively or quantitatively regulated by molecular events such as conformational change of the adhesion molecules, and/or intracellular signaling in both leukocytes and endothelial cells leading to modification of biological processes such as calcium flux, protein phosphorylation, cytoskeletal rearrangement and cell migration [2]. Intracellular signaling in endothelial cell lines has been shown for parasite lines and clones selected to adhere to ICAM-1 [7] Together, these findings underscore the complexity of the cytoadherence process in the vasculature that might not be appreciated when studied as isolated ligand-receptor interactions on recombinant proteins or transfectants [8,9,10]
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