Protection of malaria by haemoglobin S and C:
A quantitative understanding of the cytoadhesion behavior
View project details from
↪ 1st funding period (2014 – 2018)
Summary Project description 2nd funding period
Sickle cell haemoglobin (HbS) and the related haemoglobin C (HbC) bestow a survival benefit in infections with Plasmodium falciparum, the protozoan parasite causing the most virulent form of malaria in humans. The molecular mechanisms by which these structural haemoglobinopathies exert their protective function are only partly understood. Recent developments have pointed towards reduced cytoadhesion of parasitized erythrocytes to the microvascular endothelium as an underlying principle. During the previous funding period, we have shown that reduced cytoadhesion is the endpoint of a cascade of events that begins with the instability of HbS and HbC and a tendency to increased spontaneous auto-oxidation. Increased auto-oxidation of haemoglobin leads to a redox imbalance in the infected erythrocyte, which interferes with pathophysiological functions of the malaria parasite. In other studies, we have focused on the biomechanical differences between parasitized wild type and haemoglobinopathic erythrocytes. In particular, we have analyzed the membrane bending modus and the receptor density and how these two parameters affect cytoadhesive interactions.
During the next funding period, we plan to interrogate the effect of global cell elasticity on rheological properties of infected erythrocytes at the population level, using a high-speed robotic pump device (aim 1). In collaboration with Schwarz, the findings will be integrated into mathematical models in order to better understand how parasitized haemoglobinopathic erythrocytes behave in flow and under conditions of constriction as occur during passage of microcapillaries. During our previous studies, we noticed that a subpopulation of parasitized haemoglobinopathic erythrocytes binds to microvascular endothelial cells with a strength comparable to that of parasitized wild type erythrocytes. This is a potentially important observation since the strong binders could be responsible for maintaining the infection as non-adhering infected erythrocytes are thought to be cleared by the spleen. Using a home-made cell sorting device based on μ-patterns of membranes locally displaying adhesion receptors, we will first separate infected erythrocytes according to their adhesion strength under flow conditions and will subsequently investigate, and correlate, cellular and biomechanical properties with different cytoadhesion phenotypes (aim 2). The third objective will be to interrogate the cytoadhesion footprint that the various infected erythrocytes leave on microvascular endothelial cells in flow, using label-free microinterferometry and optical force sensors (in collaboration with Cavalcanti-Adam) (aim 3). This approach will help to define minimal biomechanical criteria for endothelial cell activation. We anticipate that our comprehensive approach will provide novel insights into the mechanism by which HbS and HbC protect carriers from severe malaria.