Variable antigen associated with the surface of erythrocytes infected with mature stages of Plasmodium falciparum

Rl, Coppel; Culvenor, JG; Bianco, Angelica; Pe, Crewther; Hd, Stahl; Gv, Brown; Rf, Anders; Dj, Kemp

doi:10.1016/0166-6851(86)90107-6

Cited by 86 publications

(34 citation statements)

References 32 publications

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“…This clone carries a DNA sequence which is known to reside on many different chromosomes of P.falciparum and gives a characteristic pattern of fragments for every malaria isolate examined thus far (Limpaiboon et al, 1991 the same filter as used in Figure 4 (BssHl digestion) was stripped and hybridized to a gene encoding Ag977 (unpublished data; Figure 2). In the case of all the FAC8 derived cells this probe hybridized to a band of 580 kb ( Figure 4) and using a MESA DNA probe (Coppel et al, 1986) Figure 2). nylon membrane and hybridized with the pfindrl gene probe ( Figure 5).…”

Section: Introductionmentioning

confidence: 99%

Selection for high-level chloroquine resistance results in deamplification of the pfmdr1 gene and increased sensitivity to mefloquine in Plasmodium falciparum.

et al. 1992

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A chloroquine resistant cloned isolate of Plasmodium falciparum, FAC8, which carries an amplification in the pfmdrl gene was selected for high-level chloroquine resistance, resulting in a cell line resistant to a 10-fold higher concentration of chloroquine. These cells were found to have lost the amplification in pfmdrl and to no longer over-produce the protein product termed Pglycoprotein homologue 1 (Pghl). The pfmdrl gene from this highly resistant cell line was not found to encode any amino acid changes that would account for increased resistance. Verapamil, which reverses chloroquine resistance in FAC8, also reversed high-level chloroquine resistance. Furthermore, verapamil caused a biphasic reversal of chloroquine resistance as the high-level resistance was very sensitive to low amounts of verapamil. These data suggest that over-expression of the Pglycoprotein homologue is incompatible with high levels of chloroquine resistance. In order to show that these results were applicable to other chloroquine selected lines, two additional mutants were selected for resistance to high levels of chloroquine. In both cases they were found to deamplify pfmdrl. Interestingly, while the level of chloroquine resistance of these mutants increased, they became more sensitive to mefloquine. This suggests a linkage between the copy number of the pfimdrl gene and the level of chloroquine and mefloquine resistance.

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Section: Introductionmentioning

confidence: 99%

Selection for high-level chloroquine resistance results in deamplification of the pfmdr1 gene and increased sensitivity to mefloquine in Plasmodium falciparum.

et al. 1992

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“…During the course of its intraerythocytic life, Plasmodium causes well documented biochemical and morphological changes in both pathogen and host cell (Howard 1982, Coppel 1986, Garcia et al 1997, Kirk 2001. Acidic compartments are organelles present in Plasmodium and several trypanosomatids (Docampo & Moreno 2001).…”

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Antimalarial drugs disrupt ion homeostasis in malarial parasites

Gazarini

Sigolo

Markus

et al. 2007

Mem. Inst. Oswaldo Cruz

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“…MESA is the most extensively studied of the MEC motif proteins, having been discovered more than two decades ago (13). Based on its localization to the RBC membrane and the observation that MESA competes with p55 for binding to 4.1R, MESA has been proposed to alter RBC cytoskeletal functions (57).…”

Section: Discussionmentioning

confidence: 99%

“…MESA originally was discovered as a surface antigen in infected RBCs but subsequently was shown not to be surface exposed; rather, it was associated with the RBC cytoskeleton (13,14). MESA is exported to the erythrocyte cytosol via a PEXEL-HT motif (7) and colocalizes with knobs, but it is not required for knob formation or cytoadherence (45).…”

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confidence: 99%

An Erythrocyte Cytoskeleton-Binding Motif in Exported Plasmodium falciparum Proteins

Kilili

LaCount

2011

Eukaryot Cell

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Binding of exported malaria parasite proteins to the host cell membrane and cytoskeleton contributes to the morphological, functional, and antigenic changes seen in Plasmodium falciparum-infected erythrocytes. One such exported protein that targets the erythrocyte cytoskeleton is the mature parasite-infected erythrocyte surface antigen (MESA), which interacts with the N-terminal 30-kDa domain of protein 4.1R via a 19-residue sequence. We report here that the MESA erythrocyte cytoskeleton-binding (MEC) domain is present in at least 13 other P. falciparum proteins predicted to be exported to the host cell. An alignment of the putative cytoskeleton-binding sequences revealed a conserved aspartic acid at the C terminus that was omitted from the originally reported binding domain. Mutagenesis experiments demonstrated that this aspartic acid was required for the optimal binding of MESA to inside-out vesicles (IOVs) prepared from erythrocytes. Using pulldown assays, we characterized the binding of fragments encoding the MEC domains from PFE0040c/MESA and six other proteins (PF10_0378, PFA0675w, PFB0925w, PFD0095c, PFF1510w, and PFI1790w) to IOVs. All seven proteins bound to IOVs, with MESA showing the strongest affinity in saturation binding experiments. We further examined the interaction of the MEC domain proteins with components of the erythrocyte cytoskeleton and showed that MESA, PF10_0378, and PFA0675w coprecipitated full-length 4.1R from lysates prepared from IOVs. These data demonstrated that the MEC motif is present and functional in at least six other P. falciparum proteins that are exported to the host cell cytoplasm.The pathology of the malaria parasite Plasmodium falciparum is associated with its ability to remodel the red blood cells (RBCs) it infects. Among the most dramatic changes induced by P. falciparum is the formation of thousands of protrusions (knobs) on the RBC surface, into which the P. falciparum erythrocyte membrane protein 1 (PfEMP1) is inserted (11,12,17). PfEMP1 is an antigenically variant protein that acts as a receptor for host ligands located on the endothelial lining of the vasculature or on other RBCs. Binding to endothelial cells sequesters infected RBCs in the microvasculature, which prevents the clearance of the infected RBC by the spleen and contributes to the pathogenesis of severe malaria (54). Other changes to the infected RBC include the elaboration of Golgi membrane-like vesicle stacks called Maurer's clefts and a membrane-bound tubovesicular network that together promote trafficking of molecules to and from the RBC surface (27,29). In addition to the ultrastructural changes, the functional properties of the infected RBC membrane also are affected. A new permeability pathway, which enables the transport of a range of nutrients and small molecules, is established through the insertion of parasite proteins into the RBC membrane (39, 50). The mechanical properties of the RBC membrane are altered, leading to decreased deformability and increased rigidity (37). Even the geometry o...

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Variable antigen associated with the surface of erythrocytes infected with mature stages of Plasmodium falciparum

Cited by 86 publications

References 32 publications

Selection for high-level chloroquine resistance results in deamplification of the pfmdr1 gene and increased sensitivity to mefloquine in Plasmodium falciparum.

Selection for high-level chloroquine resistance results in deamplification of the pfmdr1 gene and increased sensitivity to mefloquine in Plasmodium falciparum.

Antimalarial drugs disrupt ion homeostasis in malarial parasites

An Erythrocyte Cytoskeleton-Binding Motif in Exported Plasmodium falciparum Proteins

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