Dissecting the mechanics of erythrocyte invasion by the Plasmodium parasite

Abstract

Erythrocyte invasion by the malaria parasite P. falciparum is a complex molecular process encompassing numerous receptor host-parasite interactions with varying levels of redundancy. To date, much of the research into merozoite invasion has focused on the constituents and structure of the parasite's actin-myosin motor, which drives cell entry, and the essentiality of receptor-ligand interactions. However, despite significant recent advances in these areas of research, we still know very little about what many parasite ligands mechanistically do. Additionally, despite the fact that a number of erythrocyte receptors utilised during invasion are known to trigger cytoskeletal and biophysical changes when bound by antibodies, a potential role for signaling pathways within the erythrocyte has largely been ignored.

The work presented here, explores whether binding of parasite ligands trigger signalling events, in particular biophysical changes, that facilitate merozoite invasion. Using two biophysical techniques, real-time deformability cytometry and flicker spectroscopy, this work demonstrates that binding of the parasite ligand EBA175 to its erythrocyte receptor GPA triggers a complex set of biophysical events in the red cell leading to an increase in erythrocyte tension and a reduction in the cell's bending modulus. Combining the biophysical work with quantitative merozoite invasion assays I show that the reduction in the red cell bending modulus is directly correlated with parasite invasion efficiency. Based on the link between erythrocyte membrane biophysics and parasite invasion, I further explored how dyslipidemia affect these properties using a mouse model of hypercholesterolemia. The work presented here strongly suggests that the change in the erythrocyte bending modulus, triggered by parasite-host interactions, lowers the energy requirement for bending the red cell membrane and significantly contributes to merozoite invasion efficiency. It further raises questions about potential links between conditions which lead to high cholesterol, such as hypercholesterolemia, red cell lipid composition and malaria.