Multiscale Simulation of Malaria-Infected Erythrocytes and Spherocytes of Hereditary Spherocytosis Passing Endothelial Slits in the Spleen

Abstract

We combine a multiscale modeling approach and the Dissipative Particle Dynamics to simulate erythrocytes (red blood cells, RBCs) in circulation, and focus on the splenic clearance of healthy RBCs, malaria-infected RBCs and spherocytes in hereditary spherocytosis anemia. Our multiscale approach includes a Monte Carlo model of spectrins with domain unfolding reactions, a Brownian Dynamics model of the junctional complex with detailed protein connectivity and a whole cell finite element model with the bilayer-skeleton friction derived from measured transmembrane protein mobility. The fluid-cell interaction problem is solved using the Dissipative Particle Dynamics and a Boundary Element Method of Stokes flow. We first validate our models by predicting RBC shapes in capillary and shear flows, and compare our results of the skeleton density variation in micropipette aspiration and tank-treading frequency with experiments. Then we carry out systematic analysis of the critical conditions of RBCs passing through the endothelial slits in the spleen, including the effects of cell size, membrane stiffness, sphericity and slit size. Furthermore, we found that the skeleton density variation and the bilayer-skeleton interaction force are much larger in spherocytes than in healthy RBCs for both splenic passage and shear flow, which may lead to further bilayer loss and explain the development of hereditary spherocytosis. In addition, we also build a model of malaria-infected RBCs (iRBCs) in asexual stage, especially during ring stage using the experimentally obtained iRBC shape and rigidity. The estimated spleen retention rate of iRBCs is consistent with recent experimental data. Finally, to understand why only mature iRBCs in sexual forms (gametocytes) are observed in peripheral blood for uptake in the mosquito meal, models of gametocytes are constructed and the simulation results suggest that spleen retention is a possible mechanism.