The effects of dyslipidaemia and cholesterol modulation on erythrocyte susceptibility to malaria parasite infection

Abstract

Malaria disease commences when blood-stage parasites, called merozoites, invade human red blood cells (RBCs). Whilst the process of invasion is traditionally seen as beingentirely merozoite-driven, emerging data suggests RBC biophysical properties markedly influence invasion. Cholesterol is a major determinant of cell membrane biophysical properties. We set out to assess whether cholesterol content in the RBC membrane affects susceptibility to merozoite invasion. Here we demonstrate that RBC bending modulus (a measure of deformability) is markedly affected by artificial modulation of cholesterol content and negatively correlated with merozoite invasion efficiency. Contextualising this observation, we tested a mouse model of hypercholesterolemia and human clinical samples from patients with a range of serum cholesterol concentrations for parasite susceptibility. Hypercholesterolaemia in both human and murine subjects had little effect merozoite invasion efficiency. Furthermore, on testing, RBC cholesterol content in both murine and human hypercholesterolaemia settings was found to be unchanged from normal controls. Serum cholesterol is, therefore, unlikely to impact on RBC susceptibility to merozoite entry. Our work, however, suggests that native polymorphisms that affect RBC membrane lipid composition would be expected to affect parasite entry. This supports investigation of RBC biophysical properties in endemic settings, which may yet identify naturally protective lipidrelated polymorphisms.

A constitutive model for the remodelling erythrocyte membrane skeleton during the active invasion by the malaria merozoite

“…Previous studies have described molecular factors altering the elastic behaviour of the erythrocyte membrane [10,12]. However, the impact of the erythrocyte membrane remodelling [13] on the merozoite's invasiveness is not well understood.…”