Limited Cross-Reactivity among Domains of the Plasmodium falciparum Clone 3D7 Erythrocyte Membrane Protein 1 Family

Abstract

The var gene-encoded Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family is responsible for antigenic variation and sequestration of infected erythrocytes during malaria. We have previously grouped the 60 PfEMP1 variants of P. falciparum clone 3D7 into groups A and B/A (category A) and groups B, B/C, and C (category non-A). Expression of category A molecules is associated with severe malaria, and that of category non-A molecules is associated with uncomplicated malaria and asymptomatic infection. Here we assessed cross-reactivity among 60 different recombinant PfEMP1 domains derived from clone 3D7 by using a competition enzyme-linked immunosorbent assay and a pool of plasma from 63 malaria-exposed Tanzanian individuals. We conclude that naturally acquired antibodies are largely directed toward epitopes varying between different domains with a few, mainly category A, domains sharing cross-reactive antibody epitopes. Identification of groups of serological cross-reacting molecules is pivotal for the development of vaccines based on PfEMP1.

A Novel Domain Cassette Identifies Plasmodium falciparum PfEMP1 Proteins Binding ICAM-1 and Is a Target of Cross-Reactive, Adhesion-Inhibitory Antibodies

“…47). Parasites expressing group A PfEMP1 proteins occur predominantly among children with limited immunity (7), and IgG to this group of Ags is acquired faster than IgG to other PfEMP1 groups (48,49) and appear to be more cross-reactive (39,50). The data presented in this study underpin these earlier findings and support the hypothesis that IgG to relatively conserved and functionally important Ab epitopes in group A PfEMP1 proteins are of importance in acquisition of clinical immunity to malaria.…”

“…Recombinant ICAM-1-Fc chimera (0.2 mg/well) was added (1 h; room temperature), followed by washing and detection of bound chimera by anti-human HRP-IgG (1:3000 in blocking buffer; 1 h) or by mouse anti-human ICAM-1 (clone RR1/1; AH Diagnostics; 1:400) followed by anti-mouse HRP-IgG (DakoCytomation; 1:1000) (39). In assays of PfEMP1 domain interference of this binding, the ICAM-1-Fc chimera (2 mg/ml) was preincubated with recombinant PfEMP1 constructs (0-50 mg/ml; 1 h; room temperature).…”

Sequential, Ordered Acquisition of Antibodies to Plasmodium falciparum Erythrocyte Membrane Protein 1 Domains

“…Abs to CIDR domains were developed faster than the Abs to DBL domains, and this probably reflects that there is a broader cross-reactivity between CIDR domains than between DBL domains. This notion is supported by previous findings using competition ELISA indicating that different recombinant CIDR domains based on 3D7 sequence could out-compete each other, but that there was little cross-reactivity between 3D7 DBL domains (39). None of the children in this study was likely to have been infected with 3D7, and yet many developed Abs reacting with recombinant DBL domains based on this genome.…”

3D7-Derived Plasmodium falciparum Erythrocyte Membrane Protein 1 Is a Frequent Target of Naturally Acquired Antibodies Recognizing Protein Domains in a Particular Pattern Independent of Malaria Transmission Intensity

“…It has previously been suggested that such exchange is more likely to take place between groups B and C PfEMP1, but that some characteristics of group A PfEMP1 have leaked into these two groups (10). Based on the present and previous studies (24,29), we speculate certain PfEMP1 domains (e.g., CIDR) to be more likely exchanged and conserved than others and thus to contribute to the VSA SM phenotype of parasites causing severe malaria in individuals with little or no immunity. Such conservation and exchange of certain domains would explain the discrepancy between the results presented here and those previously seen in comparison between severe and uncomplicated malaria (13), because for a significant finding to occur, severe malaria-type domains and not full-length PfEMP1 would need to be identified before testing of a much larger number of different domain types and would probably also require a larger set of plasma samples from different individuals.…”