Cytoadhesion of Plasmodium falciparum–infected erythrocytes to chondroitin-4-sulfate is cooperative and shear enhanced

Abstract

Key Points• Cytoadhesion of parasitized erythrocytes depends on the intermolecular distance between neighboring chondroitin-4-sulfate molecules.• VAR2CSA is an allosteric adhesin that binds chondroitin-4-sulfate in a cooperative and shear stress-induced manner.Infections with the human malaria parasite Plasmodium falciparum during pregnancy can lead to severe complications for both mother and child, resulting from the cytoadhesion of parasitized erythrocytes in the intervillous space of the placenta. Cytoadherence is conferred by the specific interaction of the parasite-encoded adhesin VAR2CSA with chondroitin-4-sulfate (CSA) present on placental proteoglycans. CSA presented elsewhere in the microvasculature does not afford VAR2CSA-mediated cytoadhesion of parasitized erythrocytes. To address the placenta-specific binding tropism, we investigated the effect of the receptor/ligand arrangement on cytoadhesion, using artificial membranes with different CSA spacing intervals. We found that cytoadhesion is strongly dependent on the CSA distance, with half-maximal adhesion occurring at a CSA distance of 9 6 1 nm at all hydrodynamic conditions. Moreover, binding to CSA was cooperative and shear stress induced. These findings suggest that the CSA density, together with allosteric effects in VAR2CSA, aid in discriminating between different CSA milieus. (Blood. 2015;125(2):383-391)

Rolling Adhesion of Schizont Stage Malaria-Infected Red Blood Cells in Shear Flow

“…A similar value has indeed been reported for the PfEMP-1/CSA-bond (71). The knob density is taken to be 10/mm 2 following earlier measurements for the same strain (19). This indicates that both receptor and ligand densities might be limiting.…”

“…Early measurements reported that their density increases from $20 to 60/mm 2 from trophozoite to schizont (15), but these numbers are very variable and differ considerably between different malaria strains. For the strain used here, the knob density increases from $9 to 15/mm 2 from trophozoite to schizont (19). With a RBC surface area of A ¼ 136 mm 2 that is approximately constant over the developmental cycle (11), this corresponds to an increase of the numbers of knobs from N k z 1000-2000.…”

“…Although catch-slip bonds have been reported for leukocyte adhesion (64) and although there is evidence for shear-enhanced binding of iRBCs (19), in the absence of detailed FIGURE 1 Schematic diagram of the computational model showing a spherical (schizont) iRBC of radius R rolling in shear flow with shear rate _ g. The spatially resolved receptors on the cell surface are localized to parasite-induced knobs and can form molecular bonds with the spatially resolved ligands on the substrates, which have a uniform density. The shear force F s and the shear torque T s lead to translational velocity v and rotational velocity U, depending on the details of the spatial receptor and ligand distributions and of the bond dynamics.…”

“…Yet the basic design principle (elevated platforms for adhesion receptors distributed over a roundish cell shape) is very similar and therefore iRBC-rolling can be considered as mimicry of WBC-rolling (36). In particular, flow chamber experiments are also commonly used to study rolling adhesion of iRBCs (19,23,27,37).…”

Malaria selectively targets pregnancy receptors

“…1 M alaria is a prehistoric disease caused by Plasmodium, a genus of parasitic protozoans. Mentioned in the ancient Chinese, Greek, Sanskrit, and Roman literature, the Italian word "mal'aria" for "bad air" refers to an infection that has profoundly influenced the history of human civilization.…”