Optimization and inhibition of the adherent ability of Plasmodium falciparum-infected erythrocytes

Abstract

The vast majority of the 1-2 million malaria associated deaths that occur each year are due to anemia and cerebral malaria (the attachment of erythrocytes containing mature forms of Plasmodium falciparum to the endothelial cells that line the vascular beds of the brain). A "model system" for the study of cerebral malaria employs amelanotic melanoma cells as the "target" cells in an in vitro cytoadherence assay. Using this model system we determined that the optimum pH for adherence is 6.6 to 6.8, that high concentrations of Ca2+ (50mM) result in increased levels of binding, and that the type of buffer used influences adherence (Bis Tris > MOPS > HEPES > PIPES). We also observed that the ability of infected erythrocytes to cytoadhere varied from (erythrocyte) donor to donor. We have produced murine monoclonal antibodies against P. falciparum-infected red cells which recognize modified forms of human band 3; these inhibit the adherence of infected erythrocytes to melanoma cells in a dose-responsive fashion. Antimalarials (chloroquine, quinacrine, mefloquine, artemisinin), on the other hand, affected adherence in an indirect fashion i.e. since cytoadherence is due, in part, to the presence of knobs on the surface of the infected erythrocyte, and knob formation is dependent on intracellular parasite growth, when plasmodial development is inhibited so is knob production, and consequently adherence is ablated.

The Malaria Parasite Progressively Dismantles the Host Erythrocyte Cytoskeleton for Efficient Egress

“…P. falciparum infection reduces deformability (2) and changes the adhesive properties of the host RBC, because of the appearance of knoblike protrusions on the surface (3)(4)(5) and specialized secretion of parasite proteins into the host cell (6,7). Yet perhaps the most profound change to the RBC is its complete collapse at the end of the parasite erythrocytic cycle, as the newly replicated merozoites are released (8).…”

Impact of Highland Topography Changes on Exposure to Malaria Vectors and Immunity in Western Kenya

“…Recent studies suggested that residents of highland areas generally lack immunity to Plasmodium falciparum and are particularly vulnerable to malaria infection ( 18 – 20 ). The proportion of asymptomatic individuals is usually lower in highlands than in high-transmission areas where there is small among-season variation in P. falciparum prevalence and parasite densities ( 21 ); thus, a small increase in the abundance of vectors may lead to a significant malaria outbreak in the highlands. At high altitudes in the highlands and on hilltops, where malaria transmission intensity is low, human populations have poorly developed immunity to malaria because exposures are infrequent, and persons are vulnerable to severe clinical illness and complications from Plasmodium infection ( 22 ).…”

Evaluation of immunotherapy to reverse sequestration in the treatment of severe Plasmodium falciparum malaria

“…Cytoadherence involves infected RBC ligands interacting with host receptors. The malaria‐expressed cytoadherence ligands include pfalhesin 4 , sequestrin 5 , modified band 3 6 , 7 , the clag 9 gene product 8 and erythrocyte membrane protein 1 (PfEMP1) 9 . Adherence ligands have been associated with the knob‐like protuberances on an infected erythrocyte surface 9 .…”