A Plasma Survey Using 38 PfEMP1 Domains Reveals Frequent Recognition of the Plasmodium falciparum Antigen VAR2CSA among Young Tanzanian Children

Andrew V Oleinikov,Patrick E Duffy,Valentina V Voronkova,Robert Morrison,Michal Fried,Isaac Tyler Frye,Emily Amos,Georges Snounou

doi:10.1371/journal.pone.0031011

Abstract

PfEMP1 proteins comprise a family of variant antigens that appear on the surface of P. falciparum-infected erythrocytes and bind to multiple host receptors. Using a mammalian expression system and BioPlex technology, we developed an array of 24 protein constructs representing 38 PfEMP1 domains for high throughput analyses of receptor binding as well as total and functional antibody responses. We analyzed the reactivity of 561 plasma samples from 378 young Tanzanian children followed up to maximum 192 weeks of life in a longitudinal birth cohort. Surprisingly, reactivity to the DBL5 domain of VAR2CSA, a pregnancy malaria vaccine candidate, was most common, and the prevalence of reactivity was stable throughout early childhood. Reactivity to all other PfEMP1 constructs increased with age. Antibodies to the DBL2βC2PF11_0521 domain, measured as plasma reactivity or plasma inhibition of ICAM1 binding, predicted reduced risk of hospitalization for severe or moderately severe malaria. These data suggest a role for VAR2CSA in childhood malaria and implicate DBL2βC2PF11_0521 in protective immunity.

Highlights

Severe malaria syndromes caused by Plasmodium falciparum kill over 1 million African children each year
Multi-domain N-terminal segment (NTS)-DBL1-CIDR1 constructs bind CD36 In their native state, proteins exist in a folded form, which can create conformationally dependent epitopes and mask cryptic epitopes
Correctly folded recombinant proteins may have lower seroreactivity than unfolded proteins [17,25], which could be explained by cryptic epitopes

Summary

Introduction

Severe malaria syndromes caused by Plasmodium falciparum kill over 1 million African children each year. We assayed 561 plasma samples from 378 young children followed up to age 192 weeks in longitudinal birth cohort studies in Tanzania [24] for reactivity to 24 protein constructs representing 38 PfEMP1 domains.

Results

Conclusion