Abstract
Var2CSA, a key molecule linked with pregnancy-associated malaria (PAM), causes sequestration of Plasmodium falciparum infected erythrocytes (PEs) in the placenta by adhesion to chondroitin sulfate A (CSA). Var2CSA possesses a 300 kDa extracellular region composed of six Duffy-binding like (DBL) domains and a cysteine-rich interdomain region (CIDRpam) module. Although initial studies implicated several individual var2CSA DBL domains as important for adhesion of PEs to CSA, new studies revealed that these individual domains lack both the affinity and specificity displayed by the full-length extracellular region. Indeed, recent evidence suggests the presence of a single CSA-binding site formed by a higher-order domain organization rather than several independent binding sites located on the different domains. Here, we search for the minimal binding region within var2CSA that maintains high affinity and specificity for CSA binding, a characteristic feature of the full-length extracellular region. Accordingly, truncated recombinant var2CSA proteins comprising different domain combinations were expressed and their binding characteristics assessed against different sulfated glycosaminoglycans (GAGs). Our results indicate that the smallest region within var2CSA with similar binding properties to those of the full-length var2CSA is DBL1X-3X. We also demonstrate that inhibitory antibodies raised in rabbit against the full-length DBL1X-6ε target principally DBL3X and, to a lesser extent, DBL5ε. Taken together, our results indicate that efforts should focus on the DBL1X-3X region for developing vaccine and therapeutic strategies aimed at combating PAM.
Highlights
Pregnancy-associated malaria (PAM) causes adverse pregnancy outcomes, including anemia and hypertension in first-time pregnant women, and low birth weight due to premature delivery and fetal growth restriction, which are associated with a higher risk of fetal and neonate morbidity and mortality [1,2]
In SDS-PAGE under reducing conditions, all proteins migrated according to their expected molecular weights: 3D7-DBL1X (45 kDa), 3D7-DBL2X (53 kDa), FCR3-DBL3X (43 kDa), 3D7-DBL5e (37 kDa), 3D7-DBL1X-2X (105 kDa), FCR3-DBL3X-4e (86 kDa), 3D7-DBL1X-CIDR (134 kDa), 3D7-DBL1X-3X (176 kDa), 3D7-DBL1X-4e (215 kDa), 3D7DBL1X-5e (259 kDa), and 3D7-DBL1X-6e (300 kDa) (Fig. 1C), while under non-reducing conditions a shift in the migration of all proteins confirmed the presence of disulfide bridges (Fig. 1B)
Pregnancy-associated malaria is the consequence of Plasmodium falciparum Plasmodium falciparum-infected erythrocytes (PEs) sequestration in the intervillous space of placenta [1]
Summary
Pregnancy-associated malaria (PAM) causes adverse pregnancy outcomes, including anemia and hypertension in first-time pregnant women, and low birth weight due to premature delivery and fetal growth restriction, which are associated with a higher risk of fetal and neonate morbidity and mortality [1,2]. Gene disruption studies have clearly demonstrated that var2CSA is the primary var gene responsible for the CSA-binding phenotype, as Dvar2CSA mutant clones either did not recover the CSA-binding phenotype [15] or otherwise switched to low affinity CSA binders that no longer reacted in a gender-specific manner with multigravid sera [16]. These mutant parasites were unable to express any other ligand that promoted extensive sequestration in placental tissue [16,17]. World-wide parasite isolates analysed so far contain at least one var2CSA ortholog with an amino acid identity ranging from 54% to 94% and distinct, as well as conserved, epitopes [13,21,22,23]
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