A Two-Compartment Model of Osmotic Lysis in Plasmodium falciparum-Infected Erythrocytes

Abstract

We recently identified a voltage-dependent anion channel on the surface of human red blood cells (RBCs) infected with the malaria parasite, Plasmodium falciparum. This channel, the plasmodial erythrocyte surface anion channel (PESAC), likely accounts for the increased permeability of infected RBCs to various small solutes, as assessed quantitatively with radioisotope flux and patch-clamp studies. Whereas this increased permeability has also been studied by following osmotic lysis of infected cells in permeant solutes, these experiments have been limited to qualitative comparisons of lysis rates. To permit more quantitative examination of lysis rates, we have developed a mathematical model for osmotic fragility of infected cells based on diffusional uptake via PESAC and the two-compartment geometry of infected RBCs. This model, combined with a simple light scattering assay designed to track osmotic lysis precisely, produced permeability coefficients that match both previous isotope flux and patch-clamp estimates. Our model and light scattering assay also revealed Michaelian kinetics for inhibition of PESAC by furosemide, suggesting a 1:1 stoichiometry for their interaction.

Plasmodium falciparum-activated Chloride Channels Are Defective in Erythrocytes from Cystic Fibrosis Patients

“…Taken together, our data do not support the hypothesis raised by Desai et al (6) that the Plasmodium-activated inwardly rectifying ion channel (recently renamed PESAC (25,26)) adequately accounts for the parasite-induced increases in permeability to a broad range of solutes. Their hypothesis was based on the highly similar pharmacological profile of the inwardly rectifying chloride conductance and the new permeation pathway (6) and on the finding that the chloride conductivity of infected red blood cells, as calculated from patch clamp analysis, matched the chloride conductance calculated from chloride flux measurements (25).…”

“…Their hypothesis was based on the highly similar pharmacological profile of the inwardly rectifying chloride conductance and the new permeation pathway (6) and on the finding that the chloride conductivity of infected red blood cells, as calculated from patch clamp analysis, matched the chloride conductance calculated from chloride flux measurements (25). Our data suggest a less vital role for the inwardly rectifying chloride channel.…”

An Epigenetic Antimalarial Resistance Mechanism Involving Parasite Genes Linked to Nutrient Uptake

“…tering assay (25). Trophozoite stage-infected RBCs were enriched to Ͼ95% parasitemia by Percoll-sorbitol density gradient centrifugation, washed in 150 mM NaCl, 20 mM HEPES, 0.1 mg/ml of BSA, pH 7.4, and resuspended at 5% hematocrit.…”

Extracellular Methemoglobin Mediated Early ROS Spike Triggers Osmotic Fragility and RBC Destruction: An Insight into the Enhanced Hemolysis During Malaria

“…A number of different models have been proposed in the past to explain hemolysis with much emphasis on the steps of RBC lysis [18][19][20][21]. The earlier biochemical model proposed that RBC lysis is a two step process, initial ''sensitization'' and then actual ''lysis''.…”

“…[sensitization] but needs additional help to facilitate the efficient lysis (hemolysis) [18][19][20]. Conversion of hemoglobin to methemoglobin within RBC triggers the development of oxidative stress and causes structural membrane defects (sensitization).…”