Antigenic Differences and Conservation among PlacentalPlasmodium falciparum–Infected Erythrocytes and Acquisition of Variant‐Specific and Cross‐Reactive Antibodies

Abstract

Background. Pregnant women are infected by Plasmodium falciparum with novel antigenic phenotypes that adhere to chondroitin sulfate A (CSA) and other receptors in the placenta. The diverse and variant parasite protein P. falciparum erythrocyte membrane protein 1 (PfEMP1), which is encoded by var genes, is a ligand for CSA and a major target of antibodies associated with protective immunity.Methods. Serum samples from pregnant women exposed to malaria were tested for immunoglobulin G, adhesion-inhibitory antibodies, and agglutinating antibodies to different CSA-binding isolates expressing conserved var2csa-type genes and to parasite isolates from infected placentas. Parasite isolates also were examined to assess PfEMP1 expression, the effect of trypsin treatment of infected erythrocytes on parasite adhesion and cleavage of PfEMP1, and inhibition of adhesion by rabbit antiserum raised against a CSA-binding isolate.Results. Findings demonstrated that (1) there are significant antigenic differences between CSA-binding isolates that correspond with polymorphisms in var2csa; (2) there are differences in the properties of PfEMP1 and antibody reactivity between CSA-binding and placental isolates, which express multiple PfEMP1 forms; (3) acquired antibodies target diverse and cross-reactive epitopes expressed by CSA-binding infected erythrocytes, and cross-reactive antibodies are not necessarily cross-inhibitory; and (4) the breadth of antibody reactivity is greater among multigravidae than among primigravidae.Conclusions. Immunity may be mediated by a repertoire of antibodies to diverse and common epitopes. Strategies based on vaccination with a single domain or isolate might be hindered by antigenic diversity.

Targets of antibodies against Plasmodium falciparum–infected erythrocytes in malaria immunity

“…Western blots were performed using Triton X-100-insoluble, SDS-soluble protein extracts of trophozoite-IEs, as previously described (61,62). Triton X-100-insoluble protein extracts were resuspended in 2% SDS in PBS and separated by SDS-PAGE performed on 3%-8% Tris-Acetate Gels (Invitrogen) for PfEMP1 detection and 4%-12% Bis-Tris Gels (Invitrogen) for RIFIN and STEVOR detection.…”

Antigenic Variation in Plasmodium falciparum : Gene Organization and Regulation of the var Multigene Family

“…Detailed serological comparisons have shown that the human immunoglobulin G response against PAM appears to be highly focused on polymorphic regions in VAR2CSA (6,10,20). Significantly, sequence analysis indicates there is extensive overlap of VAR2CSA polymorphism between globally diverse parasite isolates and that polymorphic loops assume a relatively limited diversity of basic types (11,100).…”

Evidence for Globally Shared, Cross-Reacting Polymorphic Epitopes in the Pregnancy-Associated Malaria Vaccine Candidate VAR2CSA

“…Whereas numerous studies have shown that maternal antibodies are capable of recognizing geographically diverse CSAbinding isolates (4,18,24,30), more detailed serological characterizations have suggested that the human IgG response against placental isolates appears to be significantly focused on polymorphic regions in VAR2CSA (1,6,12,41). After exposure, pregnant women appear to acquire a repertoire of variant-specific antibodies, some of which cross-react with different placental isolates (5,6,30,41).…”

“…After exposure, pregnant women appear to acquire a repertoire of variant-specific antibodies, some of which cross-react with different placental isolates (5,6,30,41). Although there is still limited understanding of the antigenic relationship of different VAR2CSA alleles, sequence comparisons have revealed an extensive segmental gene relationship between different var2csa genes (8,39).…”