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. 2019 Jan 1;219(1):110-120.
doi: 10.1093/infdis/jiy467.

Cross-Species Immune Recognition Between Plasmodium vivax Duffy Binding Protein Antibodies and the Plasmodium falciparum Surface Antigen VAR2CSA

Sédami Gnidehou  1 , Catherine J Mitran  2 , Eliana Arango  3 , Shanna Banman  2 , Angie Mena  2 , Evelyn Medawar  2 , Barbara A S Lima  4 , Justin Doritchamou  5 , Jahanara Rajwani  2 , Albert Jin  2 , Kenneth Gavina  6 , Francis Ntumngia  7 , Patrick Duffy  5 , David Narum  5 , Nicaise Tuikue Ndam  8 , Morten A Nielsen  9 , Ali Salanti  9 , Flora S Kano  4 , Luzia H Carvalho  4 , John H Adams  7 , Amanda Maestre  3 , Michael F Good  10 , Stephanie K Yanow  2   6
Affiliations

Cross-Species Immune Recognition Between Plasmodium vivax Duffy Binding Protein Antibodies and the Plasmodium falciparum Surface Antigen VAR2CSA

Sédami Gnidehou et al. J Infect Dis. .

Abstract

Background: In pregnancy, Plasmodium falciparum parasites express the surface antigen VAR2CSA, which mediates adherence of red blood cells to chondroitin sulfate A (CSA) in the placenta. VAR2CSA antibodies are generally acquired during infection in pregnancy and are associated with protection from placental malaria. We observed previously that men and children in Colombia also had antibodies to VAR2CSA, but the origin of these antibodies was unknown. Here, we tested whether infection with Plasmodium vivax is an alternative mechanism of acquisition of VAR2CSA antibodies.

Methods: We analyzed sera from nonpregnant Colombians and Brazilians exposed to P. vivax and monoclonal antibodies raised against P. vivax Duffy binding protein (PvDBP). Cross-reactivity to VAR2CSA was characterized by enzyme-linked immunosorbent assay, immunofluorescence assay, and flow cytometry, and antibodies were tested for inhibition of parasite binding to CSA.

Results: Over 50% of individuals had antibodies that recognized VAR2CSA. Affinity-purified PvDBP human antibodies and a PvDBP monoclonal antibody recognized VAR2CSA, showing that PvDBP can give rise to cross-reactive antibodies. Importantly, the monoclonal antibody inhibited parasite binding to CSA, which is the primary in vitro correlate of protection from placental malaria.

Conclusions: These data suggest that PvDBP induces antibodies that functionally recognize VAR2CSA, revealing a novel mechanism of cross-species immune recognition to falciparum malaria.

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Figures

Figure 1.
Figure 1.
Human antibodies to Plasmodium vivax Duffy binding protein (PvDBP) recognize the Plasmodium falciparum surface antigen VAR2CSA. A, Sera from different populations in Colombia were tested for reactivity to full-length VAR2CSA (based on detection of the FCR3 allele) by enzyme-linked immunosorbent assay (ELISA; dilution, 1:1000). Values are expressed as mean AUs (±SD) relative to a positive control on each plate. A cutoff (stippled line) was determined for each antigen, based on the mean ODs (+2 SDs) for individual sera from the Canadian population. The percentage of samples with an AU above the cutoff is indicated for each population. AUs of the sera from the malaria-exposed groups in the clinic and community were significantly different from that for the unexposed group from Medellín, using a Dunn multiple comparisons test (P < .0001, for all comparisons between groups). B, VAR2CSA reactivity in sera positive against P. vivax MSP1 (PvMSP1) and negative against P. falciparum MSP1 (PfMSP1). Samples were collected from individuals in Colombia and Brazil and were analyzed against VAR2CSA as described in panel A. C, Colombian sera from panel B that were seropositive against VAR2CSA and with P. vivax exposure were pooled, and immunoglobulin G (IgG) was purified. Total IgG was tested in the inhibition of binding assay against a placental isolate that was adapted to in vitro culture. Total IgG was purified from the pooled sera of unexposed Colombians as control IgG. Results are expressed as the number of parasites bound to chondroitin sulfate A (CSA) from triplicates of a representative experiment. D, PvDBP antibodies underwent affinity purification from a pool of sera from Colombian men and children previously exposed to P. vivax and titrated against VAR2CSA by ELISA, with an initial IgG concentration of 12 μg/mL (1:10 dilution on the x-axis). IgG from unexposed Colombians served as the control. Data are mean ODs (±SD).
Figure 2.
Figure 2.
A Plasmodium vivax Duffy binding protein (PvDBP) mouse monoclonal antibody recognizes the Plasmodium falciparum surface antigen VAR2CSA. A, Titration of 2 PvDBP mouse monoclonal antibodies (mAbs; 3D10 and 2D10) and control immunoglobulin G1 (IgG1) against full-length VAR2CSA (FCR3) by enzyme-linked immunosorbent assay (ELISA). The concentration of the first dilution (1:50 on the x-axis) of each antibody was 8.6 μg/mL. Data are mean ODs (±SD). B, PvDBP mAb 3D10 and the isotype control (8.6 μg/mL for both) were tested against various recombinant Duffy binding–like (DBL) domains from VAR2CSA (ID1-ID2, DBL3X, DBL4ε, and DBL5ε), full-length VAR2CSA, IT4var07 CIDRα1.4, against P. falciparum MSP1 (PvMSP1), and against P. vivax MSP1 (PvMSP1) by ELISA, all coated at 0.5 μg/mL. C, red blood cells (RBCs) infected with mature P. falciparum strain CS2 parasites were fixed and costained with DAPI (blue), PvDBP mAb 3D10 (red), and a rabbit polyclonal antibody to VAR2CSA (green). Controls are shown in Supplementary Figure 2. D, Live cell images of a representative CS2-infected RBC (under bright field and with DAPI costaining) that shows costaining of PvDBP mAb 3D10 (red) and anti-VAR2CSA antibody (green).
Figure 3.
Figure 3.
Plasmodium vivax Duffy binding protein (PvDBP) monoclonal antibody (mAb) 3D10 recognizes live Plasmodium falciparum strain CS2–infected red blood cells (RBCs). CS2, a placental isolate, and NF54–chondroitin sulfate A (CSA) infected RBCs were analyzed by flow cytometry. A and B, To verify the expression of VAR2CSA, infected RBCs were stained with normal rabbit serum (A) and a polyclonal anti-VAR2CSA rabbit antibody (B), both at a 1:40 dilution. C and D, All 3 strains were stained with the immunoglobulin G1 (IgG1) isotype control (C) and PvDBP 3D10 mAb (D), both at 143 μg/mL. The percentage of infected RBCs recognized by the antibody is indicated on each plot.
Figure 4.
Figure 4.
Plasmodium vivax Duffy binding protein (PvDBP) monoclonal antibody (mAb) 3D10 blocks adhesion of infected red blood cells (RBCs) to chondroitin sulfate A (CSA). A, Controls for the inhibition of binding assay included Plasmodium falciparum strain–CS2 infected RBCs incubated with phosphate-buffered saline (PBS) alone, soluble CSA (sCSA), and sera from primigravid and multigravid women from Uganda. B–D, PvDBP mAb 3D10 was tested for inhibition of CS2 (B), a placental isolate (C), and NF54-CSA–infected RBC binding to CSA (D). Results are expressed as the number of parasites bound to CSA from replicates of a representative experiment. IgG1, immunoglobulin G1.
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