Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The malaria parasite, Plasmodium falciparum, invades the human erythrocyte through a complex interaction with erythrocyte receptors characterized by patterns of resistance to various enzymes. As invasion rates are influenced by blood group polymorphisms, we reasoned that the extremely rare rhesus null (Rh(null)) erythrocytes could be informative in characterizing receptors. The aim was to test whether the complete absence of the Rh complex from the cell membrane impacted on parasite invasion. Enzyme treatment patterns for four P. falciparum isolates were first characterised for normal Rh cells. Two isolates showed an enzyme treatment pattern not hitherto described, with resistance to neuraminidase, trypsin and chymotrypsin. In contrast, all isolates had enhanced invasion rates for the Rh(null) cell for all enzyme treatment regimens. The first finding suggests there is another pathway that P. falciparum can utilise to invade the host. We speculate that the Rh null cell membrane exposes a novel ligand defined as Receptor N.
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PMID:Invasion of Rh Null Cells by Plasmodium falciparum identifies a new invasion pathway. 1791 50

Proteins that coat Plasmodium falciparum merozoite surface and those secreted from its apical secretory organelles are considered promising candidates for the vaccine against malaria. In the present study, we have identified an asparagine rich parasite protein (PfAARP; Gene ID PFD1105w), that harbors a predicted signal sequence, a C-terminal transmembrane region and whose transcription and translation patterns are similar to some well characterized merozoite surface/apical proteins. PfAARP was localized to the apical end of the merozoites by GFP-targeting approach using an inducible, schizont-stage expression system, by immunofluorescence assays using anti-PfAARP antibodies. Immuno-electron microsopic studies showed that PfAARP is localized in the apical ends of the rhoptries in the merozoites. RBC binding assays with PfAARP expressed on COS cells surface showed that it binds to RBCs through its N-terminal region with a receptor on the RBC surface that is sensitive to trypsin and neuraminidase treatments. Sequencing of PfAARP from different P. falciparum strains as well as field isolates showed that the N-terminal region is highly conserved. Recombinant protein corresponding to the N-terminal region of PfAARP (PfAARP-N) was produced in its functional form in E. coli. PfAARP-N showed reactivity with immune sera from individuals residing in P. falciparum endemic area. The anti-PfAARP-N rabbit antibodies significantly inhibited parasite invasion in vitro. Our data on localization, functional assays and invasion inhibition, suggest a role of PfAARP in erythrocyte binding and invasion by the merozoite.
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PMID:Identification and characterization of a novel Plasmodium falciparum merozoite apical protein involved in erythrocyte binding and invasion. 1832 51

Plasmodium falciparum invasion into human erythrocytes relies on the interaction between multiple parasite ligands and their respective erythrocyte receptors. The sialic acid-independent invasion pathway is dependent on the expression of P. falciparum reticulocyte binding protein-like homologue 4 (PfRh4), as disruption of the gene abolishes the ability of parasites to switch to this pathway. We show that PfRh4 is present as an invasion ligand in culture supernatants as a 160-kDa proteolytic fragment. We confirm that PfRh4 binds to the surfaces of erythrocytes through recognition of an erythrocyte receptor that is neuraminidase resistant but trypsin and chymotrypsin sensitive. Serum antibodies from malaria-exposed individuals show reactivity against the binding domain of PfRh4. Purified immunoglobulin G raised in rabbits against the binding domain of PfRh4 blocked the binding of native PfRh4 to the surfaces of erythrocytes and inhibited erythrocyte invasion of parasites using sialic acid-independent invasion pathways and grown in neuraminidase-treated erythrocytes. Our results suggest PfRh4 is a potential vaccine candidate.
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PMID:Antibodies to reticulocyte binding protein-like homologue 4 inhibit invasion of Plasmodium falciparum into human erythrocytes. 1930 8

Proteins on the surface of the merozoite, the invasive form of the malaria parasite Plasmodium falciparum,and those secreted from its apical secretory organelles are promising vaccine candidates against blood stage malaria. In the present study, we have identified a novel parasite protein (PfDBLMSP; Gene IDPF10_0348), that harbors a predicted signal sequence, a central Duffy binding-like (DBL) domain and a secreted polymorphic antigen associated with merozoites (SPAM) domain in its C-terminal half. Transcription and translation of pfdblmsp is up-regulated specifically in schizont stage parasites, similar to other well-chararacterized merozoite proteins involved in invasion of red blood cells (RBCs). PfDBLMSPwas localized on the merozoite surface with a GFP targeting approach using schizont-stage specific expression systems, and by immunofluorescence assays of the endogenous protein. PfDBLMSP expressed on the surface of mammalian cells (COS-7) showed binding with human RBCs and this binding was sensitive to trypsin and neuraminidase treatments. The recombinant proteins corresponding to the DBL and SPAM domains showed reactivity with immune sera from individuals residing in P. falciparum endemic areas. Polymorphism in PfDBLMSP sequences from different P. falciparum strains and field isolates suggested that its DBL domain is under natural immune pressure. Our data on localization and functional assays suggest a possible role of PfDBLMSP in binding of merozoites with erythrocytes during invasion.
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PMID:A novel Plasmodium falciparum erythrocyte binding protein associated with the merozoite surface, PfDBLMSP. 1936 30

Erythrocyte invasion is central to malaria parasite replication and virulence. Plasmodium falciparum parasites use different alternative erythrocyte receptors and vary in expression of erythrocyte-binding antigenic (EBA) proteins and reticulocyte-binding protein homologues (Rh). Parasite invasion phenotypes and schizont-stage transcript expression profiles of the 8 eba and Rh protein-coding genes without internal stop codons were determined for 163 clinical isolates cultured ex vivo in The Gambia. There was extensive diversity in ability to invade erythrocytes treated with neuraminidase, trypsin, or chymotrypsin, and severe malaria isolates were less restricted by trypsin treatment than were mild malaria isolates (P = .015). Expression profiles of the eba and Rh genes showed distinct clusters indicating coordinated alternative transcription. The most divergent of 5 major clusters was dominated by Rh2b, with virtually no expression of eba175 or eba140 genes (which were dominant in the other 4 clusters). Particular transcripts were significantly correlated with parasitemia (Rh5 was positively correlated and eba140 negatively correlated; P < .01 for both) and age of patients (eba181 was positively correlated and eba175 negatively correlated; P < .001 for both) but not with invasion phenotypes or severity of malaria. Severe and mild malaria isolates were also evenly represented across the different expression clusters.
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PMID:Erythrocyte invasion and merozoite ligand gene expression in severe and mild Plasmodium falciparum malaria. 2005 Aug 6

Plasmodium falciparum is a highly lethal malaria parasite of humans. A major portion of its life cycle is dedicated to invading and multiplying inside erythrocytes. The molecular mechanisms of erythrocyte invasion are incompletely understood. P. falciparum depends heavily on sialic acid present on glycophorins to invade erythrocytes. However, a significant proportion of laboratory and field isolates are also able to invade erythrocytes in a sialic acid-independent manner. The identity of the erythrocyte sialic acid-independent receptor has been a mystery for decades. We report here that the complement receptor 1 (CR1) is a sialic acid-independent receptor for the invasion of erythrocytes by P. falciparum. We show that soluble CR1 (sCR1) as well as polyclonal and monoclonal antibodies against CR1 inhibit sialic acid-independent invasion in a variety of laboratory strains and wild isolates, and that merozoites interact directly with CR1 on the erythrocyte surface and with sCR1-coated microspheres. Also, the invasion of neuraminidase-treated erythrocytes correlates with the level of CR1 expression. Finally, both sialic acid-independent and dependent strains invade CR1 transgenic mouse erythrocytes preferentially over wild-type erythrocytes but invasion by the latter is more sensitive to neuraminidase. These results suggest that both sialic acid-dependent and independent strains interact with CR1 in the normal red cell during the invasion process. However, only sialic acid-independent strains can do so without the presence of glycophorin sialic acid. Our results close a longstanding and important gap in the understanding of the mechanism of erythrocyte invasion by P. falciparum that will eventually make possible the development of an effective blood stage vaccine.
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PMID:Complement receptor 1 is a sialic acid-independent erythrocyte receptor of Plasmodium falciparum. 2058 58

The malaria parasite Plasmodium falciparum invades human erythrocytes through multiple pathways utilizing several ligand-receptor interactions. These interactions are broadly classified in two groups according to their dependency on sialic acid residues. Here, we focus on the sialic acid-dependent pathway by using purified glycophorins and red blood cells (RBCs) to screen a cDNA phage display library derived from P. falciparum FCR3 strain, a sialic acid-dependent strain. This screen identified several parasite proteins including the erythrocyte-binding ligand-1, EBL-1. The phage cDNA insert encoded the 69-amino acid peptide, termed F2i, which is located within the F2 region of the DBL domain, designated here as D2, of EBL-1. Recombinant D2 and F2i polypeptides bound to purified glycophorins and RBCs, and the F2i peptide was found to interfere with binding of D2 domain to its receptor. Both D2 and F2i polypeptides bound to trypsin-treated but not neuraminidase or chymotrypsin-treated erythrocytes, consistent with known glycophorin B resistance to trypsin, and neither the D2 nor F2i polypeptide bound to glycophorin B-deficient erythrocytes. Importantly, purified D2 and F2i polypeptides partially inhibited merozoite reinvasion in human erythrocytes. Our results show that the host erythrocyte receptor glycophorin B directly interacts with the DBL domain of parasite EBL-1, and the core binding site is contained within the 69 amino acid F2i region (residues 601-669) of the DBL domain. Together, these findings suggest that a recombinant F2i peptide with stabilized structure could provide a protective function at blood stage infection and represents a valuable addition to a multi-subunit vaccine against malaria.
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PMID:Identification of a specific region of Plasmodium falciparum EBL-1 that binds to host receptor glycophorin B and inhibits merozoite invasion in human red blood cells. 2227 81

Plasmodium vivax is a very common but non-cultivable malaria parasite affecting large human population in tropical world. To develop therapeutic reagents for this malaria, the parasite molecules involved in host-parasite interaction need to be investigated as they form effective vaccine or drug targets. We have investigated here the erythrocyte binding activity of a group of 15 different Plasmodium vivax tryptophan rich antigens (PvTRAgs). Only six of them, named PvTRAg, PvTRAg38, PvTRAg33.5, PvTRAg35.2 PvTRAg69.4 and PvATRAg74, showed binding to host erythrocytes. That the PvTRAgs binding to host erythrocytes was specific was evident from the competitive inhibition and saturation kinetics results. The erythrocyte receptors for these six PvTRAgs were resistant to trypsin and neuraminidase. These receptors were also chymotrypsin resistant except the receptors for PvTRAg38 and PvATRAg74 which were partially sensitive to this enzyme. The cross-competition studies showed that the chymotrypsin resistant RBC receptor for each of these two proteins was different. Altogether, there seems to be three RBC receptors for these six PvTRAgs and each PvTRAg has two RBC receptors. Both RBC receptors for PvTRAg, PvTRAg69.4, PvTRAg33.5, and PvTRAg35.2 were common to all these four proteins. These four PvTRAgs also shared one of their RBC receptors with PvTRAg38 as well as with PvATRAg74. The erythrocyte binding activity of these six PvTRAgs was inhibited by the respective rabbit polyclonal antibodies as well as by the natural antibodies produced by the P. vivax exposed individuals. It is concluded that only selective few PvTRAgs show erythrocyte binding activity involving different receptor molecules which can be blocked by the natural antibodies. Further studies on these receptor and ligands may lead to the development of therapeutic reagents for P. vivax malaria.
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PMID:Erythrocyte Binding Activity Displayed by a Selective Group of Plasmodium vivax Tryptophan Rich Antigens Is Inhibited by Patients' Antibodies. 2323 92

Aotus nancymaae, the owl monkey, provides a useful laboratory model for research to develop drugs and vaccines against human falciparum malaria; however, many Plasmodium falciparum parasites are unable to invade A. nancymaae erythrocytes, rendering the parasites noninfective to the monkeys. In previous work, we identified a key polymorphism that determined the inheritance of erythrocyte invasion in a genetic cross of two P. falciparum clones that were virulent (GB4) or noninfective (7G8) to A. nancymaae. This polymorphism, an isoleucine-to-lysine polymorphism at position 204 (I204K) of the GB4 erythrocyte binding protein PfRH5, was nevertheless not found in several other P. falciparum lines that could also invade A. nancymaae erythrocytes. Alternative PfRH5 polymorphisms occur at different positions in these virulent parasites, and additional polymorphisms are found in P. falciparum parasites that cannot infect A. nancymaae. By allelic replacement methods, we have introduced the polymorphisms of these A. nancymaae-virulent or noninfective parasites at codons 204, 347, 358, 362, 410, and 429 of the endogenous PfRH5 gene in the noninfective 7G8 line. 7G8 transformants expressing the polymorphisms of the A. nancymaae-virulent parasites show neuraminidase-sensitive (sialic acid-dependent) invasion into the monkey erythrocytes, whereas 7G8 transformants expressing the PfRH5 alleles of noninfective parasites show little or no invasion of these erythrocytes. Parasites harboring PfRH5 polymorphisms 204K or 204R are also able to invade rat erythrocytes and are differentially sensitive to the removal of surface sialic acids by neuraminidase. These studies offer insights into the PfRH5 receptor-binding domain and interactions that support the invasion of various primate and rodent erythrocytes by P. falciparum.
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PMID:Various PfRH5 polymorphisms can support Plasmodium falciparum invasion into the erythrocytes of owl monkeys and rats. 2330 74

Host cell invasion by Plasmodium falciparum requires multiple molecular interactions between host receptors and parasite ligands. A family of parasite proteins, which contain the conserved thrombospondin structural repeat motif (TSR), has been implicated in receptor binding during invasion. In this study we have characterized the functional role of a TSR containing blood stage protein referred to as P. falciparum thrombospondin related apical merozoite protein (PfTRAMP). Both native and recombinant PfTRAMP bind untreated as well as neuraminidase, trypsin or chymotrypsin-treated human erythrocytes. PfTRAMP is localized in the rhoptry bulb and is secreted during invasion. Adhesion of microneme protein EBA175 with its erythrocyte receptor glycophorin A provides the signal that triggers release of PfTRAMP from the rhoptries. Rabbit antibodies raised against PfTRAMP block erythrocyte invasion by P. falciparum suggesting that PfTRAMP plays an important functional role in invasion. Combination of antibodies against PfTRAMP with antibodies against microneme protein EBA175 provides an additive inhibitory effect against invasion. These observations suggest that targeting multiple conserved parasite ligands involved in different steps of invasion may provide an effective strategy for the development of vaccines against blood stage malaria parasites.
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PMID:A thrombospondin structural repeat containing rhoptry protein from Plasmodium falciparum mediates erythrocyte invasion. 2338 21


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