Abstract
Sickle cell trait, a common hereditary blood disorder, protects carriers from severe disease in infections with the human malaria parasite Plasmodium falciparum. Protection is associated with a reduced capacity of parasitized erythrocytes to cytoadhere to the microvascular endothelium and cause vaso-occlusive events. However, the underpinning cellular and biomechanical processes are only partly understood and the impact on endothelial cell activation is unclear. Here, we show, by combining quantitative flow chamber experiments with multiscale computer simulations of deformable cells in hydrodynamic flow, that parasitized erythrocytes containing the sickle cell haemoglobin displayed altered adhesion dynamics, resulting in restricted contact footprints on the endothelium. Main determinants were cell shape, knob density and membrane bending. As a consequence, the extent of endothelial cell activation was decreased. Our findings provide a quantitative understanding of how the sickle cell trait affects the dynamic cytoadhesion behavior of parasitized erythrocytes and, in turn, endothelial cell activation.
Highlights
Sickle cell trait, a common hereditary blood disorder, protects carriers from severe disease in infections with the human malaria parasite Plasmodium falciparum
We examined the adhesion dynamics of P. falciparum-infected erythrocytes on human dermal microvascular endothelial cells (HDMECs) in flow (Fig. 1a)
HDMECs were chosen as a model substratum because they present CD36 and ICAM-121, and facilitate both dynamic and firm adhesive interactions with parasitized erythrocytes[22,23]
Summary
A common hereditary blood disorder, protects carriers from severe disease in infections with the human malaria parasite Plasmodium falciparum. Cytoadherence of parasitized erythrocytes can lead to vaso-occlusive events and impaired tissue perfusion[3] These life-threatening complications are thought to be mitigated in carriers of the sickle cell trait as the corresponding parasitized erythrocytes display a reduced capacity to cytoadhere to microvascular endothelial cells[4], other mechanisms of protection are being discussed, including modulation of the host’s immune response[5], reduced intracellular multiplication under low oxygen tension[6], and interference of parasite gene expression by host cell microRNA species[7]. It is further unclear to what extent parasitized HbAS erythrocytes activate microvascular endothelial cells and how this process depends on the red blood cell-specific cellular and mechanical properties. Endothelial cell activation is thought to potentiate sequestration of parasitized erythrocytes and, vascular obstruction through the upregulation and clustering of cytoadhesion receptors[17,18,19,20]
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