An Alternative Secretory Pathway in Plasmodium: More Questions than Answers

The malaria parasite extensively modifies the host erythrocyte. Many of these modifications are mediated by proteins that are exported from the parasite and targeted to specific locations within the infected erythrocyte. However, little is known about how the parasite targets proteins to specific locations beyond its own plasma membrane. Treatment of infected erythrocytes with brefeldin-A results in the accumulation of many exported Plasmodium proteins into a compartment that is distinct from the endoplasmic reticulum. Proteins destined for the host erythrocyte membrane, the parasitophorous vacuole, or inclusions within the erythrocyte cytoplasm accumulate in this novel compartment and co-localization studies indicate that there is a single compartment per parasite. Exported proteins only accumulate in this novel compartment if brefeldin-A treatment is concurrent with their synthesis. This novel compartment is probably a membrane-bound organelle located at the parasite periphery and may be the first step in an alternate secretory pathway that specializes in the export of proteins into the host cell. Such an alternate secretory pathway raises questions about how exported proteins are differentially targeted to this novel organelle versus the endoplasmic reticulum and the fate of exported proteins after this novel organelle. Intracellular parasites experience many barriers in their exploitation of host cells. In addition to problems associated with entering host cells, parasites must also survive in the confines of another cell. This intracellular survival involves both impeding host cell defenses and carrying out metabolic processes. Many intracellular parasites have evolved unique metabolic features to compensate for their rather esoteric environments. For example, the intraerythrocytic malaria parasite has evolved several proteases for the specific digestion of hemoglobin, as well as a polymerization mechanism to deal with the toxicity of the free heme generated by this digestion (Francis et al 1997). In addition, new permeability pathways have been described in the infected erythrocyte (this volume: Kirk, 1999). The malaria parasite also extensively modifies the cytoplasm and plasma membrane of the host erythrocyte during its intraerythrocytic stage. The electron-dense protuberances on the surface of Plasmodium falciparum-infected erythrocytes and caveola-vesicle complexes on P. vivax-infected erythrocytes are well known ultrastructural changes in the host erythrocyte (Aikawa 1977). Several distinct parasite induced compartments are also found in the cytoplasm of Plasmodium-infected erythrocytes (Gormley et al 1992, Stenzel & Kara 1989). In addition, numerous parasite antigens are localized to ill-defined inclusions within the erythrocyte cytoplasm. Ultrastructural studies suggest that these antigens are associated with the parasite-induced intraerythrocytic membranes (Hinterberg et al 1994, Martinez et al 1998). These intraerythrocytic membranes are probably extensions of the parasitophorous vacuole membrane (PVM). However, these antigens are not associated with the entire PVM, but probably associated with distinct domains of the PVM extensions as illustrated by colocalization studies (Haldar 1998). Many of these erythrocyte modifications are probably related to the metabolic demands and acquisition of nutrients by the parasite. Other alterations, such as the P. falciparum knobs, play more specialized roles in parasite survival (Crabb et al 1997). Regardless of their functions, parasite proteins exported into the host erythrocyte directly or indirectly mediate these host modifications. Furthermore, exported parasite proteins are specifically targeted to distinct locations within the infected erythrocyte. This trafficking of proteins to locations beyond the parasite plasma membrane raises