Shift in epitope dominance of IgM and IgG responses to Plasmodium falciparum MSP1 block 4

Sandra P Chang,Rose Gf Leke,Alexander Kk Kayatani,Zilka I Terrientes,Socrates Herrera,Diane W Taylor

doi:10.1186/1475-2875-9-14

Abstract

BackgroundPlasmodium falciparum merozoite surface protein-1 (MSP1) has been extensively studied as a blood-stage malaria vaccine candidate, with most work focused on the conserved 19 kDa and semi-conserved 42 kDa C-terminal regions (blocks 16-17) and the hypervariable N-terminal repeat region (block 2). However, recent genotyping studies suggest that additional regions of MSP1 may be under selective pressure, including a locus of intragenic recombination designated as block 4 within the 3' region of the gene.MethodsThe current study examined the antibody response to the two parental and two recombinant forms of block 4 and to blocks 16-17 (3D7) in study populations from Colombia, Papua New Guinea and Cameroon that differ in malaria transmission intensity and ethnic composition.ResultsIgM and IgG antibodies were detected against parental and recombinant MSP1 block 4 peptides in all three populations. Overall, 32-44% of the individuals produced IgM to one or more of the peptides, with most individuals having IgM antibodies reactive with both parental and recombinant forms. In contrast, IgG seropositivity to block 4 varied among populations (range 15-65%), with the majority of antibodies showing specificity for one or a pair of block 4 peptides. The IgG response to block 4 was significantly lower than that to blocks 16-17, indicating block 4 is subdominant. Antibodies to block 4 and blocks 16-17 displayed distinct IgG subclass biases, with block 4 responses biased toward IgG3 and blocks 16-17 toward IgG1. These patterns of responsiveness were consistently observed in the three study populations.ConclusionsProduction of antibodies specific for each parental and recombinant MSP1 block 4 allele in different populations exposed to P. falciparum is consistent with balancing selection of the MSP1 block 4 region by the immune response of individuals in areas of both low and high malaria transmission. MSP1 block 4 determinants may be important in isolate-specific immunity to P. falciparum.

Highlights

Plasmodium falciparum merozoite surface protein-1 (MSP1) has been extensively studied as a bloodstage malaria vaccine candidate, with most work focused on the conserved 19 kDa and semi-conserved 42 kDa Cterminal regions and the hypervariable N-terminal repeat region
Plasmodium falciparum merozoite surface protein 1 (MSP1) is a candidate antigen for inclusion in a blood stage malaria vaccine because it is thought to play a role in erythrocyte invasion [1]
This study examined the recognition of MSP1 block 4 by antibodies of humans exposed to P. falciparum infection in order to begin to address the potential immunological significance of MSP1 block 4 sequence variability

Summary

Introduction

Plasmodium falciparum merozoite surface protein-1 (MSP1) has been extensively studied as a bloodstage malaria vaccine candidate, with most work focused on the conserved 19 kDa and semi-conserved 42 kDa Cterminal regions (blocks 16-17) and the hypervariable N-terminal repeat region (block 2). Recent genotyping studies suggest that additional regions of MSP1 may be under selective pressure, including a locus of intragenic recombination designated as block 4 within the 3’ region of the gene. The semi-conserved and variable regions are generally dimorphic, with the prototype MSP1 alleles represented by the K1 and MAD20 parasite isolates. Exceptions to this dimorphism are tripeptide repeat sequences comprising block 2, which are of variable length and composition, and a RO33 non-repetitive block 2 variant. Sequence analysis of 34 full-length MSP1 sequences has provided no evidence of recombination in blocks 6 through 16 [4]

Methods

Results

Conclusion