Why do malaria parasites increase host erythrocyte permeability?

Abstract

Malaria parasites increase erythrocyte permeability to diverse solutes including anions, some cations, and organic solutes, as characterized with several independent methods. Over the past decade, patch-clamp studies have determined that the permeability results from one or more ion channels on the infected erythrocyte host membrane. However, the biological role(s) served by these channels, if any, remain controversial. Recent studies implicate the plasmodial surface anion channel (PSAC) and a role in parasite nutrient acquisition. A debated alternative role in remodeling host ion composition for the benefit of the parasite appears to be nonessential. Because both channel activity and the associated clag3 genes are strictly conserved in malaria parasites, channel-mediated permeability is an attractive target for development of new therapies.

Keywords: antimalarial drug discovery; clag3; erythrocyte remodeling; host–pathogen interactions; intracellular parasitism; nutrient acquisition; parasite ion channels.

Figure 1

Molecular insights into increased solute permeability after infection. (A) Structures of blasticidin S and leupeptin, antimalarial toxins that require channel-mediated uptake; notice that these toxins are large and polar. The schematic shows an infected erythrocyte with PSAC at the erythrocyte surface. Red, yellow, and blue compartments represent erythrocyte cytosol, parasitophorous vacuole, and parasite cytoplasm, respectively; Maurer’s clefts (MC) are shown in the host cytosol. After channel-mediated uptake, leupeptin inhibits proteases in the parasite digestive vacuole (DV) and other sites [87]; blasticidin S inhibits translation on parasite ribosomes (R) [88]. Resistance to these toxins is most easily acquired by modifications to PSAC that reduce toxin uptake. (B) Structure of ISPA-28, an inhibitor specific for channels from Dd2 and genetically related parasite lines. (C) Alignment of CLAG3 sequences from the indicated parasites around a highly variable motif exposed at the host cell surface. This motif may be 10 to 30 aa in length (grey shading in consensus sequence); it is especially long in the Dd2 CLAG3.1 protein, possibly accounting for specific PSAC block by ISPA-28 in this parasite. Hydrophobic residues, marked with green shading, are enriched in the conserved flanking sequences but are underrepresented in the variable motif, consistent with a soluble loop exposed at the erythrocyte surface.

Figure 2

Possible roles served by increased erythrocyte permeability. (A) Nutrient acquisition. In infected cells, nutrients can enter erythrocyte cytosol (red) by passive diffusion through PSAC at the erythrocyte membrane (RBC). These nutrients as well as those present in host cytosol cross the parasitophorous vacuolar membrane (PVM) through the PVM channel. From the vacuolar space (yellow), they are acquired at the parasite plasma membrane (PPM) through specific nutrient transporters. Maurer’s clefts (MC) may function in trafficking parasite proteins such as CLAG3 to the host cell surface [89]. A tubulovesicular network (TVN) may increase the surface area of the PVM for nutrient uptake. (B) Host cation remodeling. A Na/K pump with a 3:2 stoichiometry maintains low Na⁺ and high K⁺ concentrations in erythrocyte cytosol [90]. Slow, but steady Na⁺ uptake and K⁺ efflux through PSAC abolishes these gradients. These changes are transmitted to the parasite via the PVM channel. A Na⁺:H⁺ exchanger and a Na⁺:phosphate co-transporter have been proposed at the PPM [74,76]; these transporters could take advantage of the changes in host cation concentrations. Coupled K⁺ transporters might also utilize the gradients resulting from PSAC-mediated remodeling, but have not been proposed. Physiologically important coupling to these cation gradients is not supported by recent studies [77].