Molecular variation in Plasmodium falciparum: Polymorphic antigens of asexual erythrocytic stages

Anders, Robin F.; McColl, Damian J.; Coppel, Ross L.

doi:10.1016/0001-706x(93)90032-7

Cited by 35 publications

(24 citation statements)

References 63 publications

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“…Indeed, the high number of non-synonymous nucleotide substitutions relative to synonymous substitutions is evidence of diversifying selection 2 . Moreover, much of the amino acid polymorphism observed in antigenic genes has been mapped directly to B-and T-cell epitopes 10 . The question is: how old are these antigenic polymorphisms?…”

Section: Age Of Antigenic Allelesmentioning

confidence: 99%

The Origin of Antigenic Diversity in Plasmodium falciparum

2000

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Section: Age Of Antigenic Allelesmentioning

confidence: 99%

The Origin of Antigenic Diversity in Plasmodium falciparum

2000

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“…P. falciparum employs clonal variation too, switching the expression of protein isoforms encoded by large gene families, on the surface of infected erythrocytes (Kyes et al 2007). The parasite also possesses multiple alternative allelic forms at single loci that encode key merozoite antigens (Anders et al 1993). In both cases, the proteins provoke immune responses that are circumvented by the parasites' capacity for protein variation.…”

mentioning

confidence: 99%

Protein variation in blood-dwelling schistosome worms generated by differential splicing of micro-exon gene transcripts

DeMarco¹,

Mathieson²,

Manuel³

et al. 2010

Genome Res.

162

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Schistosoma mansoni is a well-adapted blood-dwelling parasitic helminth, persisting for decades in its human host despite being continually exposed to potential immune attack. Here, we describe in detail micro-exon genes (MEG) in S. mansoni, some present in multiple copies, which represent a novel molecular system for creating protein variation through the alternate splicing of short (#36 bp) symmetric exons organized in tandem. Analysis of three closely related copies of one MEG family allowed us to trace several evolutionary events and propose a mechanism for micro-exon generation and diversification. Microarray experiments show that the majority of MEGs are up-regulated in life cycle stages associated with establishment in the mammalian host after skin penetration. Sequencing of RT-PCR products allowed the description of several alternate splice forms of micro-exon genes, highlighting the potential use of these transcripts to generate a complex pool of protein variants. We obtained direct evidence for the existence of such pools by proteomic analysis of secretions from migrating schistosomula and mature eggs. Whole-mount in situ hybridization and immunolocalization showed that MEG transcripts and proteins were restricted to glands or epithelia exposed to the external environment. The ability of schistosomes to produce a complex pool of variant proteins aligns them with the other major groups of blood parasites, but using a completely different mechanism. We believe that our data open a new chapter in the study of immune evasion by schistosomes, and their ability to generate variant proteins could represent a significant obstacle to vaccine development.

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“…The characterization of these polymorphisms and of their distribution in P. falciparum populations suggests that they have arisen as a result of positive selection (2,14), most probably exerted by the immune response of the human host. These conclusions from population genetic studies are supported by experimental evidence that the sequence polymorphisms in AMA1 allow parasites to avoid the inhibitory effects of anti-AMA1 antibodies.…”

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confidence: 99%

The Most Polymorphic Residue on Plasmodium falciparum Apical Membrane Antigen 1 Determines Binding of an Invasion-Inhibitory Antibody

Parisi²,

et al. 2006

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Apical membrane antigen 1 (AMA1) is currently one of the leading malarial vaccine candidates. Anti-AMA1 antibodies can inhibit the invasion of erythrocytes by Plasmodium merozoites and prevent the multiplication of blood-stage parasites. Here we describe an anti-AMA1 monoclonal antibody (MAb 1F9) that inhibits the invasion of Plasmodium falciparum parasites in vitro. We show that both reactivity of MAb 1F9 with AMA1 and MAb 1F9-mediated invasion inhibition were strain specific. Site-directed mutagenesis of a fragment of AMA1 displayed on M13 bacteriophage identified a single polymorphic residue in domain I of AMA1 that is critical for MAb 1F9 binding. The identities of all other polymorphic residues investigated in this domain had little effect on the binding of the antibody. Examination of the P. falciparum AMA1 crystal structure localized this residue to a surface-exposed ␣-helix at the apex of the polypeptide. This description of a polymorphic inhibitory epitope on AMA1 adds supporting evidence to the hypothesis that immune pressure is responsible for the polymorphisms seen in this molecule.

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Molecular variation in Plasmodium falciparum: Polymorphic antigens of asexual erythrocytic stages

Cited by 35 publications

References 63 publications

The Origin of Antigenic Diversity in Plasmodium falciparum

The Origin of Antigenic Diversity in Plasmodium falciparum

Protein variation in blood-dwelling schistosome worms generated by differential splicing of micro-exon gene transcripts

The Most Polymorphic Residue on Plasmodium falciparum Apical Membrane Antigen 1 Determines Binding of an Invasion-Inhibitory Antibody

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