Abstract
The asexual reproduction cycle of Plasmodium falciparum, the parasite responsible for severe malaria, occurs within red blood cells. A merozoite invades a red cell in the circulation, develops and multiplies, and after about 48 hours ruptures the host cell, releasing 15–32 merozoites ready to invade new red blood cells. During this cycle, the parasite increases the host cell permeability so much that when similar permeabilization was simulated on uninfected red cells, lysis occurred before ∼48 h. So how could infected cells, with a growing parasite inside, prevent lysis before the parasite has completed its developmental cycle? A mathematical model of the homeostasis of infected red cells suggested that it is the wasteful consumption of host cell hemoglobin that prevents early lysis by the progressive reduction in the colloid-osmotic pressure within the host (the colloid-osmotic hypothesis). However, two critical model predictions, that infected cells would swell to near prelytic sphericity and that the hemoglobin concentration would become progressively reduced, remained controversial. In this paper, we are able for the first time to correlate model predictions with recent experimental data in the literature and explore the fine details of the homeostasis of infected red blood cells during five model-defined periods of parasite development. The conclusions suggest that infected red cells do reach proximity to lytic rupture regardless of their actual volume, thus requiring a progressive reduction in their hemoglobin concentration to prevent premature lysis.
Highlights
Plasmodium falciparum, Pf, is responsible for the most severe form of malaria in humans, representing a major cause of morbidity and mortality, especially among children
The parasite Plasmodium falciparum is responsible for severe malaria in humans
The 48 hour asexual reproduction cycle of the parasite within red blood cells is responsible for the symptoms in this disease
Summary
Plasmodium falciparum, Pf, is responsible for the most severe form of malaria in humans, representing a major cause of morbidity and mortality, especially among children. The pathology of malaria is caused by the intraerythrocytic stage of the parasite cycle. Invasion of a red blood cell (RBC) by a Pf merozoite converts a metabolically languid, hemoglobin-filled cell lacking intracellular organelles and structures, into a complex double cell, with a eukaryotic organism growing and multiplying inside, protected from immune attack. Staines et al [8] showed that if uninfected human RBCs were permeabilized to the same extent the uninfected cells would hemolyze by the unbalanced net gain of NaCl and osmotic water over a shorter time-course than that needed for parasite maturation and exit. Is the integrity of parasitized cells preserved for the duration of the intraerythrocytic cycle, considering that they have a parasite growing to a substantial volume inside?
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