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Protection against severe malaria by hemoglobin S and C: A quantitative understanding of the cytoadhesion behavior of Plasmodium falciparum infected erythrocytes

Lansche, Christine

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Abstract

To avoid clearance by the spleen, P. falciparum-infected erythrocytes adhere to the microvascular endothelial cells lining the blood vessels and sequester in the microvasculature of vital organs. Cytoadhesion results in reduced blood perfusion and inflammatory endothelial cell activation. While the parasite matures during the intraerythrocytic cycle, the infected erythrocyte undergoes a series of modifications including altered morphology, reduced deformability and increased adhesiveness. These properties govern the cytoadherence process and determine the dynamic adhesion behavior under physiological flow conditions. Several red blood cell polymorphisms, including sickle hemoglobin and hemoglobin C, have been associated with protection against severe malaria and malaria-related death. The mechanisms underlying this protection are poorly understood but it might be conferred, in part, by the reduced binding capability of infected erythrocytes to microvascular endothelial cells. Here, we quantitatively compared the adhesion dynamics of infected wild-type and sickle cell trait erythrocytes, at different parasite developmental stages, using flow chamber assays. Differences in the dynamic adhesion behavior were observed for trophozoite and schizont-stages. While a discoid shape in early stage caused flipping of the infected cell, an almost spherical cell at the late stage of the intraerythrocytic cycle results in a regular rolling motion. We further showed that changes in mechanical and adhesive properties of infected sickle cell trait erythrocytes resulted in substantial differences in the flipping and rolling dynamics, relative to infected wild-type erythrocytes, which led to a reduced contact time and predicted contact area to the endothelial cells as well as a reduced firm adherence. As a consequence of the differential firm and dynamic adhesion behavior, infected sickle trait-erythrocytes were less likely to activate microvascular endothelial cells, which in turn, might reduce the pathology observed in sickle cell trait individuals infected with P. falciparum. Overall, our findings improve the understanding of the protection mechanism against severe malaria conferred by sickle hemoglobin.

Item Type: Dissertation
Supervisor: Lanzer, Prof. Dr. Michael
Place of Publication: Heidelberg
Date of thesis defense: 11 May 2018
Date Deposited: 28 May 2018 06:52
Date: 2018
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 570 Life sciences
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