Switches in expression of Plasmodium falciparum var genes correlate with changes in antigenic and cytoadherent phenotypes of infected erythrocytes.

Parasitization by malaria-inducing Plasmodium falciparum leads to structural, biochemical, and mechanical modifications to the host red blood cells (RBCs). To study these modifications, we investigate two intrinsic indicators: the refractive index and membrane fluctuations in P. falciparum-invaded human RBCs (Pf-RBCs). We report experimental connections between these intrinsic indicators and pathological states. By employing two noninvasive optical techniques, tomographic phase microscopy and diffraction phase microscopy, we extract three-dimensional maps of refractive index and nanoscale cell membrane fluctuations in isolated RBCs. Our systematic experiments cover all intraerythrocytic stages of parasite development under physiological and febrile temperatures. These findings offer potential, and sufficiently general, avenues for identifying, through cell membrane dynamics, pathological states that cause or accompany human diseases.

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Refractive index maps and membrane dynamics of human red blood cells parasitized by Plasmodium falciparum.

The malaria parasite is a unicellular eukaryotic organism which, during the course of its complex life cycle, invades the red blood cells of its vertebrate host. As it grows and multiplies within its host blood cell, the parasite modifies the membrane permeability and cytosolic composition of the host cell. The intracellular parasite is enclosed within a so-called parasitophorous vacuolar membrane, tubular extensions of which radiate out into the host cell compartment. Like all eukaryote cells, the parasite has at its surface a plasma membrane, as well as having a variety of internal membrane-bound organelles that perform a range of functions. This review focuses on the transport properties of the different membranes of the malaria-infected erythrocyte, as well as on the role played by the various membrane transport systems in the uptake of solutes from the extracellular medium, the disposal of metabolic wastes, and the origin and maintenance of electrochemical ion gradients. Such systems are of considerable interest from the point of view of antimalarial chemotherapy, both as drug targets in their own right and as routes for targeting cytotoxic agents into the intracellular parasite.

https://www.physiology.org/doi/pdf/10.1152/physrev.2001.81.2.495

Membrane Transport in the Malaria-Infected Erythrocyte

RELATIVE protection against Plasmodium falciparum malaria afforded to heterozygous carriers of the sickle-cell gene is now the accepted mechanism for the high frequency of the gene in areas where malaria is (or was) common1–3. However, the cellular mechanisms whereby Hb S protects the red cell against the malarial parasite are still not fully understood. We have compared the rates of invasion and growth of P. falciparum in normal red cells and in those of individuals with the sickling disorders, in both aerobic conditions and conditions of reduced oxygen tension. As a result of these studies, we suggest a possible mechanism for the protection of sickle-cell heterozygotes against P. falciparum malaria.

Cellular mechanism for the protective effect of haemoglobin S against P. falciparum malaria.

Malaria during the first pregnancy causes a high rate of fetal and neonatal death. The decreasing susceptibility during subsequent pregnancies correlates with acquisition of antibodies that block binding of infected red cells to chondroitin sulfate A (CSA), a receptor for parasites in the placenta. Here we identify a domain within a particular Plasmodium falciparum erythrocyte membrane protein 1 that binds CSA. We cloned a var gene expressed in CSA-binding parasitized red blood cells (PRBCs). The gene had eight receptor-like domains, each of which was expressed on the surface of Chinese hamster ovary cells and was tested for CSA binding. CSA linked to biotin used as a probe demonstrated that two Duffy-binding-like (DBL) domains (DBL3 and DBL7) bound CSA. DBL7, but not DBL3, also bound chondroitin sulfate C (CSC) linked to biotin, a negatively charged sugar that does not support PRBC adhesion. Furthermore, CSA, but not CSC, blocked the interaction with DBL3; both CSA and CSC blocked binding to DBL7. Thus, only the DBL3 domain displays the same binding specificity as PRBCs. Because protective antibodies present after pregnancy block binding to CSA of parasites from different parts of the world, DBL-3, although variant, may induce cross-reactive immunity that will protect pregnant women and their fetuses.

https://www.pnas.org/content/pnas/96/22/12743.full.pdf

M.E. Smalley

Papers

Separation of viable schizont-infected red cells of Plasmodium falciparum from human blood.