Binding of Plasmodium falciparum 175-kilodalton erythrocyte binding antigen and invasion of murine erythrocytes requires N-acetylneuraminic acid but not its O-acetylated form

Klotz, F.; Orlandi, Palmer A.; Reuter, Gerd; Cohen, Stuart J.; Haynes, J. David; Schauer, Roland; Howard, Russell J.; Palese, Peter; Miller, Louis H.

doi:10.1016/0166-6851(92)90199-t

Cited by 86 publications

(43 citation statements)

References 30 publications

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“…falciparum merozoites also invade mouse erythrocytes, and PfEBA-175 can bind to mouse erythrocytes (12). Therefore, we assayed the binding of the recombinant PfEBA-175II F2 protein to mouse erythrocytes.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Three Pichia pastoris -Expressed Plasmodium falciparum Merozoite Proteins as a Combination Vaccine against Infection with Blood-Stage Parasites

Zhang

2005

Infect Immun

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Because invasion of erythrocytes by Plasmodium falciparum merozoites involves multiple receptor-ligand interactions, it may be necessary to develop a multivalent malaria vaccine that is comprised of distinct parasite ligands. PfAMA-1, PfMSP1, and PfEBA-175 are merozoite proteins that play important roles in invasion. We have constructed a PfCP-2.9 chimeric protein consisting of PfAMA-1 and PfMSP1 and tested it for immunogenicity in animal models and humans. The F2 subdomain of PfEBA-175 (PfEBA-175II F2) was identified as the binding domain for glycophorin A on erythrocytes. In this study, we used the codon frequencies of the yeast Pichia pastoris to redesign and synthesize a gene encoding the F2 domain. We found that the codon-optimized gene was expressed at a high level in P. pastoris as a soluble protein with a yield of about 300 mg/liter. The expressed protein was able to bind normal erythrocytes but not those treated with neuraminidase or trypsin. Moreover, the protein was recognized by the sera of malaria patients and was highly immunogenic in mice, rabbits, and rhesus monkeys. Immunoglobulin G isolated from both immunized rabbits and monkeys inhibited in vitro parasite growth. Immunization of animals with a combination of PfEBA-175II F2 and PfCP-2.9 did not result in antigen (Ag) competition in animals. Moreover, antibodies to both PfEBA-175II F2 and PfCP-2.9, isolated from rabbits immunized with both constructs, inhibited parasite growth in vitro. The combination of high yield, functional folding, antibody inhibition, and lack of Ag competition provides support for inclusion of these merozoite proteins in a combination vaccine against infection with blood-stage parasites.Plasmodium falciparum and Plasmodium vivax are the causative agents of the majority of malaria cases in the world today. Of the two, P. falciparum is responsible for the most virulent form of the disease, causing over 2 million deaths per year, usually in children under 5 years of age. Malaria infections have traditionally been treated by chemotherapy. Another approach has been to use insecticides against the Anopheles sp. mosquito vectors that transfer the parasites between hosts. Because of the emergence and rapid spread of drug-resistant parasites and insecticide-resistant mosquitoes, there is an urgent need for the development of new tools to control malaria. Vaccination is one such tool that may control and even eradicate the disease from the world. Based on the life cycle of the parasite, merozoite invasion of host erythrocytes is an optimal target for vaccines against infection with blood-stage parasites. However, merozoite invasion is a complex process involving several steps. The initial step requires species-specific interactions between erythrocyte receptors and parasite ligands. Disruption of these interactions would, in principle, prevent invasion and all of the clinical manifestations of infection. The invasion of human erythrocytes by P. vivax requires recognition of the Duffy blood group antigen (Ag) (11,22), while invasio...

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Section: Discussionmentioning

confidence: 99%

Evaluation of Three Pichia pastoris -Expressed Plasmodium falciparum Merozoite Proteins as a Combination Vaccine against Infection with Blood-Stage Parasites

Zhang

2005

Infect Immun

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“…Erythrocyte-binding antigen 175 kDa (EBA-175), expressed on the merozoite surface, is involved in P. falciparum binding to erythrocytes. [1][2][3][4][5] In animal models, immunization with synthetic EBA-175 peptides encompassing amino acids 1062 to 1103 elicits antibodies that inhibit merozoite invasion by 80% in vitro. These antibodies appear to act by preventing EBA-175 binding to erythrocytes.…”

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confidence: 99%

Imbalanced Distribution of Plasmodium falciparum EBA-175 Genotypes Related to Clinical Status in Children from Bakoumba, Gabon

Touré¹,

Bisseyé²,

Mavoungou³

2006

Clinical Medicine & Research

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Objective: The erythrocyte binding antigen 175 kDa (EBA-175) of Plasmodium falciparum is one of the major ligands for red blood cell invasion by merozoites. EBA-175 is a dimorphic antigen but the role that dimorphism plays in host parasite interaction is not fully understood. In this study, we sought to determine the distribution of EBA-175 genotypes and its pathogenetic influence. Methods:The nested polymerase chain reaction was used to determine the genotypes of P. falciparum isolates from asymptomatic and symptomatic Gabonese children.Results: CAMP strains (C-segment) and FCR-3 strains (F-segment) were found in 13/50 (26%) and 19/50 (38%) symptomatic children, respectively and in 16/66 (24%) and 46/66 (70%) asymptomatic children, respectively. The prevalence of mixed C-/F-infection was 18/50 (36%) and 4/66 (6%) in symptomatic and asymptomatic children, respectively. Conclusions:These results show that mixed C-/F-infection is associated with clinical malaria (χ 2 , P <0.01) and may have important therapeutic implications. The antigenic diversity of Plasmodium falciparum is the main obstacle to antimalarial vaccine development. Erythrocyte-binding antigen 175 kDa (EBA-175), expressed on the merozoite surface, is involved in P. falciparum binding to erythrocytes. [1][2][3][4][5] In animal models, immunization with synthetic EBA-175 peptides encompassing amino acids 1062 to 1103 elicits antibodies that inhibit merozoite invasion by 80% in vitro. These antibodies appear to act by preventing EBA-175 binding to erythrocytes. 6 In addition, a significant reduction in parasitemia was recently reported in monkeys immunized with EBA-175 is composed of 7 regions (region I-VII) and possesses 2 cysteine-rich segments (F1 and F2) located at the N-terminus in region II (figure 1). These cysteine-rich segments, F1 and F2, are responsible for glycophorin A binding to the erythrocyte membrane 4 and contain a very small number of polymorphic regions. EBA-175 region III is located in the central part of the gene, and genomic studies of two P. falciparum strains revealed two highly dimorphic segments in region III,8,9 Dimorphism is referred to as the F-fragment in the FCR-3 strain and the C-fragment in the CAMP strain. The two segments are inserted at different positions of region III and differ in length by 27 amino acids. These two alleles are both conserved, and Plasmodium merozoites, which are haploid, can possess one or the other, but not both.The role of EBA-175 antigen dimorphism in host-parasite interactions is not fully understood. Preliminary evidence suggests that the initial molecular interaction involves binding of the conserved domain (region II of EBA-175) to glycophorin A sialic acid residues, followed by proteolytic cleavage of EBA-175 and binding of the dimorphic C-and F-segments to the glycophorin A backbone. 8,9 Likewise, the role of this dimorphism in acquired protective immunity to field strains is not known. It was recently shown that EBA-175 is able to use

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“…P. falciparum uses a 175 kDa sialic acid binding protein ligand known as erythrocyte binding antigen-175 (EBA-175) for erythrocyte invasion. [1][2][3][4] The gene encoding EBA-175 has been sequenced from both the FCR3 and CAMP strains of P. falciparum. [5][6][7] While it is now well established that EBA-175 is a dimorphic antigen, the role that dimorphism plays in host-parasite interactions (including putative differences in red blood cell invasion efficiency) remains unclear.…”

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Analysis of Human Antibodies to Erythrocyte Binding Antigen 175 Peptide 4 of Plasmodium falciparum

Touré¹,

Deloron²,

Migot-Nabias³

2006

Clinical Medicine & Research

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Binding of Plasmodium falciparum 175-kilodalton erythrocyte binding antigen and invasion of murine erythrocytes requires N-acetylneuraminic acid but not its O-acetylated form

Cited by 86 publications

References 30 publications

Evaluation of Three Pichia pastoris -Expressed Plasmodium falciparum Merozoite Proteins as a Combination Vaccine against Infection with Blood-Stage Parasites

Evaluation of Three Pichia pastoris -Expressed Plasmodium falciparum Merozoite Proteins as a Combination Vaccine against Infection with Blood-Stage Parasites

Imbalanced Distribution of Plasmodium falciparum EBA-175 Genotypes Related to Clinical Status in Children from Bakoumba, Gabon

Analysis of Human Antibodies to Erythrocyte Binding Antigen 175 Peptide 4 of Plasmodium falciparum

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