Abstract
BackgroundPregnancy-associated malaria (PAM) is a serious consequence of the adhesion to the placental receptor chondroitin sulfate A (CSA) of Plasmodium falciparum-infected erythrocytes (PE) expressing the large cysteine-rich multi-domain protein var2CSA. Women become resistant to PAM, and develop strain-transcending immunity against CSA-binding parasites. The identification of var2CSA regions that could elicit broadly neutralizing and adhesion-blocking antibodies is a key step for the design of prophylactic vaccine strategies.Methodology Escherichia coli expressed var2CSA DBL domains were refolded and purified prior to immunization of mice and a goat. Protein-G-purified antibodies were tested for their ability to block FCR3CSA-infected erythrocytes binding to placental (BeWo) and monkey brain endothelial (ScC2) cell lines using a flow cytoadhesion inhibition assay mimicking closely the physiological conditions present in the placenta at shear stress of 0.05 Pa. DBL5-ε, DBL6-ε and DBL5-6-ε induced cross-reactive antibodies using Alum and Freund as adjuvants, which blocked cytoadhesion at values ranging between 40 to 96% at 0.5 mg IgG per ml. Importantly, antibodies raised against recombinant DBL5-ε from 3 distinct parasites genotypes (HB3, Dd2 and 7G8) showed strain-transcending inhibition ranging from 38 to 64% for the heterologuous FCR3CSA.ConclusionsUsing single and double DBL domains from var2CSA and Alum as adjuvant, we identified recombinant subunits inducing an immune response in experimental animals which is able to block efficiently parasite adhesion in a flow cytoadhesion assay that mimics closely the erythrocyte flow in the placenta. These subunits show promising features for inclusion into a vaccine aiming to protect against PAM.
Highlights
Plasmodium falciparum-infected erythrocytes (PE) sequester in the placenta by adhering to chondroitin sulfate A (CSA) expressed on the surface of human syncytiotrophoblasts [1]
Using single and double DBL domains from var2CSA and Alum as adjuvant, we identified recombinant subunits inducing an immune response in experimental animals which is able to block efficiently parasite adhesion in a flow cytoadhesion assay that mimics closely the erythrocyte flow in the placenta
These subunits show promising features for inclusion into a vaccine aiming to protect against Pregnancy-associated malaria (PAM)
Summary
Plasmodium falciparum-infected erythrocytes (PE) sequester in the placenta by adhering to chondroitin sulfate A (CSA) expressed on the surface of human syncytiotrophoblasts [1]. Several DBL domains are linked to CSA binding [11], the expression of full length recombinant var2CSA (exon 1) suggest that high affinity binding to CSA requires the cooperation of several domains [12,13] Disruption of this gene leads to the irreversible loss of binding to CSA, pointing to this molecule as the prime target for intervention strategies for PAM [14]. Several recent publications have reported some progress into this direction [16,17,18] In these studies, the evaluation of cytoadhesion inhibition has been based on assays using purified non-placental sources of CSA bound to plastic dishes (static assays). Pregnancy-associated malaria (PAM) is a serious consequence of the adhesion to the placental receptor chondroitin sulfate A (CSA) of Plasmodium falciparum-infected erythrocytes (PE) expressing the large cysteine-rich multidomain protein var2CSA. The identification of var2CSA regions that could elicit broadly neutralizing and adhesion-blocking antibodies is a key step for the design of prophylactic vaccine strategies
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