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. 2019 Aug 13;18(1):273.
doi: 10.1186/s12936-019-2905-9.

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

Emily M Stucke  1 , Amadou Niangaly  2 , Andrea A Berry  1 , Jason A Bailey  3 , Drissa Coulibaly  2 , Amed Ouattara  1 , Kirsten E Lyke  1 , Matthew B Laurens  1 , Antoine Dara  2 , Matthew Adams  1 , Jozelyn Pablo  4 , Algis Jasinskas  4 , Rie Nakajima  4 , Albert E Zhou  1 , Sonia Agrawal  1 , DeAnna J Friedman-Klabanoff  1 , Shannon Takala-Harrison  1 , Bourema Kouriba  2 , Abdoulaye K Kone  2 , J Alexandra Rowe  5 , Ogobara K Doumbo  2 , Philip L Felgner  4 , Mahamadou A Thera  2 , Christopher V Plowe  6 , Mark A Travassos  7
Affiliations

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

Emily M Stucke et al. Malar J. .

Abstract

Background: 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. 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).

Methods: A 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.

Results: Malian 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.

Conclusions: Larger 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.

Keywords: Immunity; Malaria; Microarray; PfEMP1; Plasmodium falciparum; Seroreactivity; var genes.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Heat map of seroreactivity to 9 PfEMP1 DBL-α tags and their parent DBL-CIDR head structures for sera from 35 Malian children, 18 adults, and 11 malaria-naïve controls, with each protein fragment separated by row, including pre-season seroreactivity and peak- or post-season seroreactivity. Each column displays the profile of one serum sample. Seroreactivities of PfEMP1 protein fragments were ordered from least to most reactive parent DBL-CIDR head structures. Individual serum samples within each subgroup were ordered from least to most seroreactive for all PfEMP1 protein fragments. Grey indicates no seroreactivity, black is low to moderate seroreactivity, and red denotes high seroreactivity to probed fragments, measured by fluorescence intensity. Seroreactivity of malaria-naïve controls was used to determine serorecognition of protein fragments by malaria exposed children and adults. PfEMP1, Plasmodium falciparum erythrocyte membrane protein-1; DBL, Duffy binding-like; CIDR, cysteine-rich interdomain region
Fig. 2
Fig. 2
Seroprevalence of DBL-α tag fragments and parent DBL-CIDR head structures recognized at pre-season for each PfEMP1 in children and adults. Paediatric sera recognized a discordant proportion of the DBL-α tag and parent DBL-CIDR head structure for two PfEMP1s, PF3D7_0632500 and PF3D7_0317400. Adult sera recognized discordant proportions of DBL-α tag and parent DBL-CIDR head structure for three PfEMP1s, PF3D7_1100200, PF3D7_0632500, and PF3D7_0808700. (*P < 0.05, **P < 0.01; ***P < 0.001. The McNemar’s test was used to compare tags and head structures within paediatric and adults groups. For comparisons between adults and children, the Chi square test was used.) PfEMP1, Plasmodium falciparum erythrocyte membrane protein-1; DBL, Duffy binding-like; CIDR, cysteine-rich interdomain region
Fig. 3
Fig. 3
Serorecognition and seroreactivity patterns of Malian children (top) and adults (bottom) for 36 protein fragments of nine 3D7 PfEMP1 antigens. Each DBL-α tag of a PfEMP1 antigen is the first fragment shown. Group serorecognized fragments are indicated in red, while blue stripes indicate increased seroreactivity of a fragment over a malaria season from pre-season to peak season for children and from pre-season to post-season for adults. PfEMP1, Plasmodium falciparum erythrocyte membrane protein-1; DBL, Duffy binding-like; CIDR, cysteine-rich interdomain region; ATS, acidic terminal segment
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