Hierarchical, Domain Type-Specific Acquisition of Antibodies to Plasmodium falciparum Erythrocyte Membrane Protein 1 in Tanzanian Children

Abstract

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a variant antigen expressed on the surface of malaria-infected erythrocytes. PfEMP1 attaches to the vascular lining and allows infected erythrocytes to avoid filtration through the spleen. Each parasite genome encodes about 60 different PfEMP1 variants, each PfEMP1 comprises several domains in its extracellular region, and the PfEMP1 repertoire in different parasites contains domain types that are serologically cross-reactive. In this longitudinal study, we followed 672 children living in an area of high malaria transmission during the first years of life and compared the acquisitions of antibodies to 32 Duffy-binding ligand-like (DBL) domains representing different types. For each child, we determined whether an antibody response to each domain was acquired before, after, or at the same time as responses to each of the other domains. We next used this information to calculate population-level odds ratios to measure the odds that antibodies to a given domain were acquired before antibodies to other domains. Odds ratios for 269 of the 496 possible domain combinations were statistically significant. Thus, the sequence in which individuals acquire antibodies to different PfEMP1 domains is ordered, and children in areas of endemicity first acquire antibodies to particular PfEMP1 domains encoded by the so-called group A and B/A var genes. The results imply that anti-PfEMP1 antibodies effectively structure PfEMP1 expression and play a major role in limiting parasite multiplication in the blood.

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.…”

A restricted subset ofvargenes mediates adherence ofPlasmodium falciparum-infected erythrocytes to brain endothelial cells

“…The fact that most DC8 var genes have mixed features (UpsB promoter and group A coding features) could limit gene recombination with other group A or group B genes and favor the evolution of specialized adhesion properties within group B/A genes. Significantly, DC8 var products tend to be among the first PfEMP1s expressed in early childhood infections (15,16), indicating they may encode unique adhesion properties that confer a growth advantage in malaria-naive children. This study demonstrates that DC8 var products can encode binding activity for brain endothelium.…”

“…Whereas most PfEMP1 proteins bind CD36, group A and the related group B/A have a distinct protein head structure from other var groups (8,9) and do not bind CD36 (13,14). Group A and B/A proteins also tend to be among the first PfEMP1 proteins expressed in early childhood infections (15)(16)(17)(18) and have been associated with more severe infections (18)(19)(20)(21), but whether they have affinity for brain endothelium is unknown. Studies of malaria during pregnancy have demonstrated how a single var gene, VAR2CSA, is primarily responsible for placenta binding (22)(23)(24).…”

B-Cell Responses to Pregnancy-Restricted and -Unrestricted Plasmodium falciparum Erythrocyte Membrane Protein 1 Antigens in Ghanaian Women Naturally Exposed to Malaria Parasites

“…In contrast, FV6 and FV60 are encoded by var genes that are transcribed and translated independent of pregnancy, and they represent rosetting PfEMP1 proteins thought to be involved in the pathogenesis of severe malaria in childhood (31). People living in areas with stable transmission of P. falciparum parasites are thought to be exposed regularly to parasites expressing this type of PfEMP1 proteins (32,33,64,65).…”