Serologic responses to the PfEMP1 DBL-CIDR head structure may be a better indicator of malaria exposure than those to the DBL-\u03b1 tag

Emily M Stucke,Amed Ouattara,Philip L Felgner,Deanna Friedman-Klabanoff ,Rie Nakajima,Mahamadou A Théra ,Christopher V Plowe,Andrea A Berry,J Alexandra Rowe,Ogobara K Doumbo,Abdoulaye K Koné ,Jason A Bailey,Jozelyn Pablo,Antoine Dara,Matthew B Laurens,Sonia Agrawal,Algis Jasinskas,Shannon Takala-Harrison,Matthew Adams,Kirsten E Lyke,Bouréma Kouriba ,Amadou Niangaly,Albert E Zhou,Drissa Coulibaly,Mark A Travassos

doi:10.1186/s12936-019-2905-9

Abstract

BackgroundPlasmodium falciparum erythrocyte membrane protein-1 (PfEMP1) antigens play a critical role in host immune evasion. Serologic responses to these antigens have been associated with protection from clinical malaria, suggesting that antibodies to PfEMP1 antigens may contribute to natural immunity. The first N-terminal constitutive domain in a PfEMP1 is the Duffy binding-like alpha (DBL-α) domain, which contains a 300 to 400 base pair region unique to each particular protein (the DBL-α “tag”). This DBL-α tag has been used as a marker of PfEMP1 diversity and serologic responses in malaria-exposed populations. In this study, using sera from a malaria-endemic region, responses to DBL-α tags were compared to responses to the corresponding entire DBL-α domain (or “parent” domain) coupled with the succeeding cysteine-rich interdomain region (CIDR).MethodsA protein microarray populated with DBL-α tags, the parent DBL-CIDR head structures, and downstream PfEMP1 protein fragments was probed with sera from Malian children (aged 1 to 6 years) and adults from the control arms of apical membrane antigen 1 (AMA1) vaccine clinical trials before and during a malaria transmission season. Serological responses to the DBL-α tag and the DBL-CIDR head structure were measured and compared in children and adults, and throughout the season.ResultsMalian serologic responses to a PfEMP1’s DBL-α tag region did not correlate with seasonal malaria exposure, or with responses to the parent DBL-CIDR head structure in either children or adults. Parent DBL-CIDR head structures were better indicators of malaria exposure.ConclusionsLarger PfEMP1 domains may be better indicators of malaria exposure than short, variable PfEMP1 fragments such as DBL-α tags. PfEMP1 head structures that include conserved sequences appear particularly well suited for study as serologic predictors of malaria exposure.

Highlights

Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP1) antigens play a critical role in host immune evasion
Fluorescence intensities to DBL-α tags and their parent DBL-cysteine-rich interdomain region (CIDR) head structures were measured using sera collected from Malian children and adults and North American malaria-naïve adult controls (Fig. 1)
For two of the nine PfEMP1 antigens, a discordant proportion of paediatric sera recognized the DBL-α tags compared to the proportion recognizing the corresponding parent DBL-CIDR head structure (PF3D7_0632500: P < 0.0001, PF3D7_01240600: P = 0.04, McNemar’s test; Fig. 2)

Summary

Introduction

Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP1) antigens play a critical role in host immune evasion Serologic responses to these antigens have been associated with protection from clinical malaria, suggesting that antibodies to PfEMP1 antigens may contribute to natural immunity. The first N-terminal constitutive domain in a PfEMP1 is the Duffy binding-like alpha (DBL-α) domain, which contains a 300 to 400 base pair region unique to each particular protein (the DBL-α “tag”). This DBL-α tag has been used as a marker of PfEMP1 diversity and serologic responses in malaria-exposed populations. A subsequent study of seroreactivity to 3D7 strain PfEMP1 antigens found that sera from children with cerebral malaria or severe malarial anaemia did not differ in recognition of DBL-α tags compared to sera from matched uncomplicated malaria controls in Bandiagara, Mali, but did with respect to larger extracellular PfEMP1 fragments [5]

Methods

Results

Discussion

Conclusion