Dataset Information

Primary structure of the variable region of monoclonal antibody 2B10, capable of inducing anti-idiotypic antibodies that recognize the C-terminal region of MSA-1 of Plasmodium falciparum.

ABSTRACT: Previously, we reported on the properties of a monoclonal antibody, 2B10, which has the same determinant on the human erythrocyte as MSA-1 of Plasmodium falciparum (FCR3 strain); the binding of both ligands to erythrocyte receptors was totally sialic acid dependent. In this work, rabbit anti-2B10 idiopathic antibodies were generated. The anti-idiotypic antibodies recognized both the erythrocyte binding site of 2B10 and the C-terminal region of MSA-1 (amino acids 1047 to 1640); they were able to inhibit 2B10 and MSA-1 binding to erythrocytes and partially prevent P. falciparum merozoites from invading erythrocytes. The utility of 2B10 in the study of the interaction between MSA-1 and human erythrocytes prompted us to determine the nucleotide and deduced amino acid sequences of its VH and VL regions. The data show that the 2B10 VH region is part of the J558 family and is especially homologous to BALB/c anti-nitrophenyl monoclonal antibody 21.1.43; the VL region belongs to the VK1 subgroup and comes from the same genomic locus as (NZB x W)F1 anti-DNA and C57BL anti-dextran monoclonal antibodies BXW-14 and 42.48.12.2, respectively. Most of the differences among the VH and VL segments are located in CDR1 and -3. The binding site of 2B10 contains both negatively and positively charged amino acid residues. The amino acid sequences of the 2B10 VH region and a region of MSA-1 from the Wellcome strain of P. falciparum (amino acids 1002 to 1115) share 43% similarity, and the amino acid sequences between the 2B10 VL region and another segment of the same MSA-1 (amino acids 1247 to 1394) share 48% similarity. We conclude that the interactions between erythrocyte receptors and their ligands, 2B10 and MSA-1, are related and that the C-terminal region of MSA-1 is the erythrocyte binding domain.

SUBMITTER: Su S

PROVIDER: S-EPMC173763 | biostudies-literature | 1996 Jan

REPOSITORIES: biostudies-literature

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Primary structure of the variable region of monoclonal antibody 2B10, capable of inducing anti-idiotypic antibodies that recognize the C-terminal region of MSA-1 of Plasmodium falciparum.

Su S S Yang S S Ding R R Davidson E A EA

Infection and immunity 19960101 1

Previously, we reported on the properties of a monoclonal antibody, 2B10, which has the same determinant on the human erythrocyte as MSA-1 of Plasmodium falciparum (FCR3 strain); the binding of both ligands to erythrocyte receptors was totally sialic acid dependent. In this work, rabbit anti-2B10 idiopathic antibodies were generated. The anti-idiotypic antibodies recognized both the erythrocyte binding site of 2B10 and the C-terminal region of MSA-1 (amino acids 1047 to 1640); they were able to ...[more]

PMID: 8557359

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Project description:Plasmodium falciparum malaria parasites, living in red blood cells, express proteins of the erythrocyte membrane protein-1 (PfEMP1) family on the red blood cell surface. The binding of PfEMP1 molecules to human cell surface receptors mediates the adherence of infected red blood cells to human tissues. The sequences of the 60 PfEMP1 genes in each parasite genome vary greatly from parasite to parasite, yet the variant PfEMP1 proteins maintain receptor binding. Almost all parasites isolated directly from patients bind the human CD36 receptor. Of the several kinds of highly polymorphic cysteine-rich interdomain region (CIDR) domains classified by sequence, only the CIDR1alpha domains bind CD36. Here we describe the CD36-binding portion of a CIDR1alpha domain, MC179, as a bundle of three alpha-helices that are connected by a loop and three additional helices. The MC179 structure, containing seven conserved cysteines and 10 conserved hydrophobic residues, predicts similar structures for the hundreds of CIDR sequences from the many genome sequences now known. Comparison of MC179 with the CIDR domains in the genome of the P. falciparum 3D7 strain provides insights into CIDR domain structure. The CIDR1alpha three-helix bundle exhibits less than 20% sequence identity with the three-helix bundles of Duffy-binding like (DBL) domains, but the two kinds of bundles are almost identical. Despite the enormous diversity of PfEMP1 sequences, the CIDR1alpha and DBL protein structures, taken together, predict that a PfEMP1 molecule is a polymer of three-helix bundles elaborated by a variety of connecting helices and loops. From the structures also comes the insight that DBL1alpha domains are approximately 100 residues larger and that CIDR1alpha domains are approximately 100 residues smaller than sequence alignments predict. This new understanding of PfEMP1 structure will allow the use of better-defined PfEMP1 domains for functional studies, for the design of candidate vaccines, and for understanding the molecular basis of cytoadherence.

Project description:The malaria vaccine candidate RTS,S/AS01 (GSK Vaccines) induces high IgG concentration against the circumsporozoite protein (CSP) of Plasmodium falciparum. In human vaccine recipients circulating anti-CSP antibody concentrations are associated with protection against infection but appear not to be the correlate of protection. However, in a humanized mouse model of malaria infection prophylactic administration of a human monoclonal antibody (MAL1C), derived from a RTS,S/AS01-immunized volunteer, directed against the CSP repeat region, conveyed full protection in a dose-dependent manner suggesting that antibodies alone are able to prevent P. falciparum infection when present in sufficiently high concentrations. A competition ELISA was developed to measure the presence of MAL1C-like antibodies in polyclonal sera from RTS,S/AS01 vaccine recipients and study their possible contribution to protection against infection.MAL1C-like antibodies present in polyclonal vaccine-induced sera were evaluated for their ability to compete with biotinylated monoclonal antibody MAL1C for binding sites on the capture antigen consisting of the recombinant protein encompassing 32 NANP repeats of CSP (R32LR). Serum samples were taken at different time points from participants in two RTS,S/AS01 vaccine studies (NCT01366534 and NCT01857869). Vaccine-induced protection status of the study participants was determined based on the outcome of experimental challenge with infected mosquito bites after vaccination. Optimal conditions were established to reliably detect MAL1C-like antibodies in polyclonal sera. Polyclonal anti-CSP antibodies and MAL1C-like antibody content were measured in 276 serum samples from RTS,S/AS01 vaccine recipients using the standard ELISA and MAL-1C competition ELISA, respectively. A strong correlation was observed between the results from these assays. However, no correlation was found between the results of either assay and protection against infection.The competition ELISA to measure MAL1C-like antibodies in polyclonal sera from RTS,S/AS01 vaccine recipients was robust and reliable but did not reveal the elusive correlate of protection.

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Project description:BackgroundThe South West Pacific nation of Papua New Guinea has intense year round transmission of Plasmodium falciparum on the coast and in the low-lying inland areas. Local heterogeneity in the epidemiology of malaria suggests that parasites from multiple locations will need to be surveyed to define the population biology of P. falciparum in the region. This study describes the population genetics of P. falciparum in thirteen villages spread over four distinct catchment areas of Papua New Guinea.MethodsTen microsatellite loci were genotyped in 318 P. falciparum isolates from the parasite populations of two inland catchment areas, namely Wosera (number of villages (n) = 7) and Utu (n = 1) and; and two coastal catchments, Malala (n = 3) and Mugil (n = 3). Analysis of the resultant multilocus haplotypes was done at different spatial scales (2-336 km) to define the genetic diversity (allelic richness and expected heterozygosity), linkage disequilibrium and population structure throughout the study area.ResultsAlthough genetic diversity was high in all parasite populations, it was also variable with a lower allelic richness and expected heterozygosity for inland populations compared to those from the more accessible coast. This variability was not correlated with two proxy measures of transmission intensity, the infection prevalence and the proportion multiple infections. Random associations among the microsatellite loci were observed in all four catchments showing that a substantial degree of out-crossing occurs in the region. Moderate to very high levels of population structure were found but the amount of genetic differentiation (FST) did not correlate with geographic distance suggesting that parasite populations are fragmented. Population structure was also identified between villages within the Malala area, with the haplotypes of one parasite population clustering with the neighbouring catchment of Mugil.ConclusionThe observed population genetics of P. falciparum in this region is likely to be a consequence of the high transmission intensity combined with the isolation of human and vector populations, especially those located inland and migration of parasites via human movement into coastal populations. The variable genetic diversity and population structure of P. falciparum has important implications for malaria control strategies and warrants further fine scale sampling throughout Papua New Guinea.

Dataset Information

Primary structure of the variable region of monoclonal antibody 2B10, capable of inducing anti-idiotypic antibodies that recognize the C-terminal region of MSA-1 of Plasmodium falciparum.

Publications

Primary structure of the variable region of monoclonal antibody 2B10, capable of inducing anti-idiotypic antibodies that recognize the C-terminal region of MSA-1 of Plasmodium falciparum.

Similar Datasets

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