Host cell remodeling by pathogens: the exomembrane system in Plasmodium-infected erythrocytes

Abstract

Malaria is caused by infection of erythrocytes by parasites of the genus Plasmodium To survive inside erythrocytes, these parasites induce sweeping changes within the host cell, one of the most dramatic of which is the formation of multiple membranous compartments, collectively referred to as the exomembrane system. As an uninfected mammalian erythrocyte is devoid of internal membranes, the parasite must be the force and the source behind the formation of these compartments. Even though the first evidence of the presence these of internal compartments was obtained over a century ago, their functions remain mostly unclear, and in some cases completely unknown, and the mechanisms underlying their formation are still mysterious. In this review, we provide an overview of the different parts of the exomembrane system, describing the parasitophorous vacuole, the tubovesicular network, Maurer's clefts, the caveola-vesicle complex, J dots and other mobile compartments, and the small vesicles that have been observed in Plasmodium-infected cells. Finally, we combine the data into a simplified view of the exomembrane system and its relation to the alterations of the host erythrocyte.

Keywords: exomembrane system; host–parasite interaction; malaria; pathogenesis; plasmodium.

Figure 1.

Overview of the elements of the exomembrane system that have been described in the literature. Not all parts have been described in all Plasmodium species, and some parts are species-specific. CVC- caveola-vesicle complex; TVN - tubovesicular network

Figure 2.

Four potential scenarios to explain the formation of the PVM during invasion of host erythrocytes. The PVM may be derived solely from the host membrane (A) or the parasite (B). Alternatively, host and parasite components may both contribute directly to the forming PVM (C). As a fourth possibility, the erythrocyte may donate membrane to form the PVM with parasite lipids acting to replenish this translocation of host cell membrane (D). Host phospholipids are indicated in black, parasite-derived phospholipids are indicated in blue.

Figure 3.

Model of host cell modification through the exomembrane system. (A) In newly invaded (young) parasites, the parasite is surrounded by a PVM that contains indentations (forming the ‘necklace of beads’). Protein export and nutrient uptake occurs through EXP2. MCs are still mobile and a prominent TVN is present. Clag3 is exported but nutrient uptake through the PSAC does not yet occur. (B) After 20–24 h, hemoglobin uptake through the cytostome initiates and the MCs become tethered to the cytoskeleton or erythrocyte membrane through MAHRP2, allowing transport of membrane proteins from the MC to the surface of the erythrocyte. Transmembrane proteins are transported through the erythrocyte cytosol to the MCs by J dots. Transfer of proteins from the MCs to the erythrocyte surface occurs via 25 nm vesicles. (C) As the parasite matures, all the MCs become tethered, knobs are formed and an accessory factor for Clag3 is exported to activate the PSAC.