Transport pathways in the malaria-infected erythrocyte: characterization and their use as potential targets for chemotherapy

Abstract

The intraerythrocytic malarial parasite is involved in an extremely intensive anabolic activity while it resides in its metabolically quiescent host cell. The necessary fast uptake of nutrients and the discharge of waste product, are guaranteed by parasite-induced alterations of the constitutive transporters of the host cell and the production of new parallel pathways. The membrane of the host cell thus becomes permeable to phospholipids, purine bases and nucleosides, small non-electrolytes, anions and cations. When the new pathways are quantitatively unimportant, classical inhibitors of native transporters can be used to inhibit parasite growth. Several compounds were found to effectively inhibit the new pathways and consequently, parasite growth. The pathways have also been used to introduce cytotoxic agents. The parasitophorous membrane consists of channels which are highly permeable to small solutes and display no ion selectivity. Transport of some cations and anions across the parasite membrane is rapid and insensitive to classical inhibitors, and in some cases it is mediated by specific antiporters which respond to their respective inhibitors. Macromolecules have been shown to reach the parasitophorous space through a duct contiguous with the host cell membrane, and subsequently to be endocytosed at the parasite membrane. The simultaneous presence of the parasitophorous membrane channels and the duct, however, is incompatible with experimental evidences. No specific inhibitors were found as yet that would efficiently inhibit transport through the channels or the duct.

Coenzyme A biosynthesis: an antimicrobial drug target

“…3, the uptake occurs via the 'new permeability pathways' (NPP) induced in the erythrocyte membrane by the maturing parasite (Saliba et al, 1998). These NPP have a broad specificity and confer upon the host cell membrane an increased permeability to a range of low-molecular-weight solutes including various nutrients, metabolic wastes and inorganic ions (Ginsburg et al, 1983(Ginsburg et al, , 1985Cabantchik, 1990;Ginsburg, 1994;Kirk et al, 1994). By contrast, normal uninfected erythrocytes lack the NPP and do not appear to express a functional pantothenate transporter.…”

Plasmodium berghei-infection induces volume-regulated anion channel-like activity in human hepatoma cells

“…These alterations allow the transport of structurally unrelated molecules and can contribute to parasite survival by modulating nutrient uptake, waste removal and volume and ion regulation. For these reasons, some of the transport pathways that underlie these processes have been proposed as antimalarial targets (Ginsburg, 1994; Staines et al ., 2005). Most recently, it has been shown that the electrophysiological technique of patch‐clamp can be used to measure altered transport activity in infected red blood cells (Staines et al ., 2004a; Staines et al ., 2007).…”

Intracellular calcium and pH conditions of cultured cells infected with Eimeria bovis or E. separata

“…A more recent model suggests that the extension of the PVM acts as a molecular sieve that allows the selective entry of speci®c nutrients such as adenosine, glutamate, and orotic acid (Lauer et al 1997). In addition, the observation that Ca 2+ does not equilibrate between the vacuolar space and the extracellular medium (Ginsburg 1994) argues against the existence of a nonselective duct in P. falciparum-infected erythrocytes. Although the evolutionary conservation of biochemical and physiological functions of the PVM formed by dierent apicomplexan parasites has been assumed by many researchers, recent data suggest that dierences may exist, depending on the type of host cell involved and on the genus of the parasite (Lingelbach and Joiner 1998).…”