Quantifying the biophysical characteristics of Plasmodium-falciparum -parasitized red blood cells in microcirculation

Abstract

The pathogenicity of Plasmodium falciparum (Pf) malaria results from the stiffening of red blood cells (RBCs) and its ability to adhere to endothelial cells (cytoadherence). The dynamics of Pf-parasitized RBCs is studied by three-dimensional mesoscopic simulations of flow in cylindrical capillaries in order to predict the flow resistance enhancement at different parasitemia levels. In addition, the adhesive dynamics of Pf-RBCs is explored for various parameters revealing several types of cell dynamics such as firm adhesion, very slow slipping along the wall, and intermittent flipping. The parasite inside the RBC is modeled explicitly in order to capture phenomena such as "hindered tumbling" motion of the RBC and the sudden transition from firm RBC cytoadherence to flipping on the endothelial surface. These predictions are in quantitative agreement with recent experimental observations, and thus the three-dimensional modeling method presented here provides new capabilities for guiding and interpreting future in vitro and in vivo studies of malaria.adhesion | erythrocyte | malaria | mechanical properties | dissipative particle dynamics R ed blood cells parasitized by Plasmodium falciparum (Pf-RBCs) undergo irreversible changes in structure and biophysical characteristics, which can lead to drastically altered blood circulation. The membrane shear modulus of infected RBCs may increase up to ten-fold causing capillary occlusions (1, 2), thereby resulting in substantial increase in resistance to blood flow. Such effects may be intensified due to the enhanced cytoadherence of Pf-RBCs to the vascular endothelium (3-6). This adherence of Pf-RBCs is believed to be the main cause of bleeding complications in cerebral malaria due to blockages of small vessels in the brain (7). Unlike the extensive research on leukocytes, very few in vitro experiments (8-11) Recent progress in multiscale numerical modeling (12-14) allows us to model soft matter, and RBCs in particular, at sufficient detail, i.e., simulating nanometer scales while simultaneously capturing the large scale dynamics. We have developed and validated a Dissipative Particle Dynamics (DPD) model (12, 14-16) that can accurately simulate the properties and dynamic behavior of healthy RBCs as well as Pf-RBCs. The multiscale model can represent a RBC at the spectrin level with 30,000 points (17) or at a coarser level with 500 points by proper scaling of the physiologically correct parameters (12, 14, 15); hence, no ad hoc calibration is required. The predictive capability of the DPD model has been demonstrated in comparisons with microfluidic experiments that probe controlled pressure-velocity relationships of (healthy) RBC flow through microchannels whose inner openings mimic the smallest dimensions for RBC passage in the microvasculature (16). In addition, we have extended the adhesive dynamics model of (18,19) to the DPD framework, and validated it by simulating the adhesive dynamics of leukocytes for which extensive experimental results exist (20,21). In summary, ...

Probing vasoocclusion phenomena in sickle cell anemia via mesoscopic simulations

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

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