Disease relevance of VAR

• The profound changes in the morphology, antigenicity, and functional properties of the host erythrocyte membrane induced by intraerythrocytic parasites of the human malaria Plasmodium falciparum are poorly understood at the molecular level [1].
• Since antiplasmodial agents that inhibit parasite growth through erythrocyte membrane modifications must be regarded as unsuitable as leads for development of new antimalarial drugs, care must be exercised in the interpretation of results of screening of plant extracts and natural product libraries by an in vitro Plasmodium toxicity assay [2].
• Symptomatic children also had the highest immunoglobulin G (IgG) reactivities to conserved P. falciparum erythrocyte membrane protein 1 and "Pfalhesin" (band #3) peptides, indicating that such IgG antibodies are stimulated by acute disease but are lost rapidly after the disease episode [3].
• These signaling cascades may have important influences on in vivo malarial infection, as well as on erythrocyte membrane flexibility and adhesiveness in sickle cell anemia [4].
• Four P. falciparum strains, including a multi-drug-resistant strain (MDR-K), a drug-sensitive strain (FCR-3), a erythrocyte membrane sialic acid-independent strain (7G8) and a strain isolated from a cerebral malaria patient (CM-87) were equally susceptible to treatment with a phosphorothioate oligomer [5].

High impact information on VAR

• This structure contains the knob-associated histidine-rich protein (KAHRP) and the adhesion receptor P. falciparum erythrocyte membrane protein 1 [6].
• The binding is mediated by the antigenically variant erythrocyte-membrane-protein-1 (PfEMP-1), which is encoded by members of the P. falciparum var gene family [7].
• Region II, which contains a cysteine-rich motif, and native EBA-175 bind specifically to glycophorin A, but not to glycophorin B, on the erythrocyte membrane [8].
• Upon induction of gametogenesis, Pfs2400 partitions between the gamete plasmalemma and the degenerating erythrocyte membrane [9].
• RESA within merozoites was largely soluble in the nonionic detergent Triton X-100, but was insoluble in this detergent when associated with the erythrocyte membrane [10].

Chemical compound and disease context of VAR

• The levels of erythrocyte membrane sialic acid from 17 patients with Plasmodium falciparum malaria and 1 with Plasmodium vivax malaria, in Papua New Guinea, have been compared with 9 uninfected controls [11].
• Both saponin and ammonium chloride produced hemolysis of uninfected and infected erythrocytes, but failed to separate host erythrocyte membrane from the parasite, regardless of its stage [12].

Biological context of VAR

• Our results indicate that the internalization of NDB-PC was not because of endocytosis but rapid transbilayer lipid flip-flop at the infected erythrocyte membrane, followed by monomer diffusion to the parasite [13].
• Truncation of the C-terminal end of PfEMP3 by transfection prevents distribution of this large (>300 kDa) protein around the membrane but does not disrupt trafficking of the protein from the parasite to the cytoplasmic face of the erythrocyte membrane [14].
• The antigenic differences were shown to result from antigenic variation of the parasite-encoded protein, the P. falciparum erythrocyte membrane protein 1 [15].
• Virulence of Plasmodium falciparum is associated with the expression of variant surface antigens designated PfEMP1 (P. falciparum erythrocyte membrane protein 1) that are encoded by a family of var genes [16].
• Parasites with this deletion did not express the variant surface agglutination phenotype and the putative asexual cytoadherence ligand designated P. falciparum erythrocyte membrane protein 1, which has recently been shown to undergo antigenic variation [17].

Anatomical context of VAR

• Infected erythrocytes also bind to endothelial cells, and this interaction is mediated by the parasite-derived variant erythrocyte membrane protein PfEMP1, which is encoded by the var gene family [18].
• The high mortality of Plasmodium falciparum malaria is the result of a parasite ligand, PfEMP1 (P. falciparum) erythrocyte membrane protein 1), on the surface of infected red blood cells (IRBCs), which adheres to the vascular endothelium and causes the sequestration of IRBCs in the microvasculature [19].
• By cryo-thin-section immunoelectron microscopy we identified organelles involved in the transit of Pf EMP through the erythrocyte cytoplasm to the internal face of the erythrocyte membrane where the protein is associated with electron-dense material under knobs [1].
• These results, together with the modulation of release by osmotic stress, suggest a pathway of parasite release that features a biochemically altered erythrocyte membrane that folds after pressure-driven rupture of membranes [20].
• These daughter cells are released upon parasitophorous vacuole and erythrocyte membrane rupture [21].

Associations of VAR with chemical compounds

• In a previous study (1990. J. Biol. Chem. 265:6562-6568), we noted that xanthine oxidase rapidly and completely depleted hypoxanthine in human erythrocytes, not by crossing the erythrocyte membrane, but rather by creating a concentration gradient which facilitated hypoxanthine efflux [22].
• Sialic acid and a trypsin-sensitive erythrocyte membrane component are important for invasion by P. falciparum parasites [23].
• The adhesion of Plasmodium falciparum-infected erythrocytes to chondroitin sulfate A is mediated by P. falciparum erythrocyte membrane protein 1 [24].
• In addition to the knob protein, which was previously shown to be associated with protrusions on the host erythrocyte membrane, a major glycoprotein of parasite origin was identified on the surface membrane of schizonts [25].
• Erythrocyte membrane proteins were analyzed by polyacrylamide gel electrophoresis and autoradiography [26].

Physical interactions of VAR

• Here we report the identification of a var gene transcribed in association with binding to CSA and present evidence that the P. falciparum erythrocyte membrane protein 1 product of the gene is the parasite ligand mediating CSA binding [24].

Other interactions of VAR

• As the presence of KAHRP at the erythrocyte membrane is necessary for cytoadherence in vivo, our findings have implications for the development of new therapies for mitigating the severity of malaria infection [27].
• The mature-parasite-infected erythrocyte surface antigen (MESA) of Plasmodium falciparum associates with the erythrocyte membrane skeletal protein, band 4.1 [28].
• Here we express epitope-tagged versions of the 2TM proteins in transgenic NF54 parasites and present evidence that the Stevor and Pfmc-2TM families are exported to the erythrocyte membrane, thus supporting the hypothesis that host immune pressure drives antigenic diversity within the loop [29].
• Thus, the induced permeability pathways in the host erythrocyte membrane and the parasite choline transporter described here form a cooperative transport system that shows great promise for the selective targeting of new agents for the chemotherapy of malaria [30].
• HABPs 31191 and 31178 recognized 56 and 26 kDa receptors on erythrocyte membrane and inhibited in vitro Plasmodium falciparum merozoite invasion of erythrocytes by between 27% and 46% at 200 microg ml(-1) concentration, suggesting that these MSP-6 protein peptides play a possible role in the invasion process [31].

Analytical, diagnostic and therapeutic context of VAR

• Here we report on the identification by single-cell reverse transcriptase PCR and cDNA cloning of the adhesive ligand P. falciparum erythrocyte membrane protein 1 (PfEMP1) [32].
• However, antibodies to P. coatneyi did not cross-react with P. falciparum RESA in erythrocyte membrane immunofluorescence assay and dot immunoblot analysis, suggesting that different immunogenic epitopes are present on the two molecules [33].
• To identify such proteases, soluble cytosolic extract of isolated trophozoites/schizonts was incubated with erythrocyte membrane ghosts or spectrin-actin depleted inside-out vesicles, which were then analyzed by SDS-PAGE [34].
• Serial sections of mature parasites fixed and stained by various methods for transmission electron microscopy reveal areas of apparent membrane continuity between the erythrocyte membrane and the parasitophorous vacuolar membrane that surrounds the parasite, that could leave the parasites exposed to the external medium [35].
• These vesicle complexes were often associated with and closely abutted the erythrocyte membrane, but were apparently prevented from fusing by the aluminium fluoride treatment, making their capture by electron microscopy possible [36].

References