Structural and Immunological Correlations between the Variable Blocks of the VAR2CSA Domain DBL6ε from Two Plasmodium falciparum Parasite Lines

Gangnard, Stéphane; Badaut, Cyril; Ramboarina, Stephanié; Baron, Bruno; Ramdani, Tarik; Gamain, B; Deloron, Philippe; Lewit-Bentley, Anita; Bentley, G.A.

doi:10.1016/j.jmb.2013.02.014

Cited by 20 publications

(20 citation statements)

References 47 publications

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“…Different dilution curves obtained against VAR2CSA-derived antigens suggested that both arrays were composed of antigens with different degrees of immunoreactivity. DBL3X and DBL5Ɛ domains were more recognized by malaria-exposed pregnant women than DBL6Ɛ, in accordance with previous studies showing that DBL3X and DBL5Ɛ are more conserved [24,54] than the C-terminal domain DBL6Ɛ [55,56]. Aminoacid variability obtained by the alignment of VAR2CSA sequences from parasites in different geographic area also showed low variability for DBL3X and DBL5Ɛ (entropy DBL3X = 0.197, entropy DBL5Ɛ = 0.208) compared with DBL6Ɛ (entropy = 0.522).…”

Section: Discussionsupporting

confidence: 91%

Multiplexing detection of IgG against Plasmodium falciparum pregnancy-specific antigens

et al. 2017

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BackgroundPregnant women exposed to Plasmodium falciparum generate antibodies against VAR2CSA, the parasite protein that mediates adhesion of infected erythrocytes to the placenta. There is a need of high-throughput tools to determine the fine specificity of these antibodies that can be used to identify immune correlates of protection and exposure. Here we aimed at developing a multiplex-immunoassay to detect antibodies against VAR2CSA antigens.Methods and findingsWe constructed two multiplex-bead arrays, one composed of 3 VAR2CSA recombinant-domains (DBL3X, DBL5Ɛ and DBL6Ɛ) and another composed of 46 new peptides covering VAR2CSA conserved and semi-conserved regions. IgG reactivity was similar in multiplexed and singleplexed determinations (Pearson correlation, protein array: R2 = 0.99 and peptide array: R2 = 0.87). IgG recognition of 25 out of 46 peptides and all recombinant-domains was higher in pregnant Mozambican women (n = 106) than in Mozambican men (n = 102) and Spanish individuals (n = 101; p<0.05). Agreement of IgG levels detected in cryopreserved plasma and in elutions from dried blood spots was good after exclusion of inappropriate filter papers. Under heterogeneous levels of exposure to malaria, similar seropositivity cutoffs were obtained using finite mixture models applied to antibodies measured on pregnant Mozambican women and average of antibodies measured on pregnant Spanish women never exposed to malaria. The application of the multiplex-bead array developed here, allowed the assessment of higher IgG levels and seroprevalences against VAR2CSA-derived antigens in women pregnant during 2003–2005 than during 2010–2012, in accordance with the levels of malaria transmission reported for these years in Mozambique.ConclusionsThe multiplex bead-based immunoassay to detect antibodies against selected 25 VAR2CSA new-peptides and recombinant-domains was successfully implemented. Analysis of field samples showed that responses were specific among pregnant women and dependent on the level of exposure to malaria. This platform provides a high-throughput approach to investigating correlates of protection and identifying serological markers of exposure for malaria in pregnancy.

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Section: Discussionsupporting

confidence: 91%

Multiplexing detection of IgG against Plasmodium falciparum pregnancy-specific antigens

et al. 2017

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“…First, parasites which adhere to the receptor chondroitin sulfate A (CSA) on placental capillary endothelia in pregnant women express a particular variant of PfEMP1, termed VAR2CSA, that is encoded by only one or a few similar var gene types in each parasite genome [67,68] , although there is considerable antigenic diversity due to allelic polymorphism within populations. A vaccine which either covered VAR2CSA polymorphism within a multi-allelic formulation or which focused responses on conserved epitopes might protect against pregnancy-associated malaria, and this prospect has led to structural studies to design proteins based on particular domains eliciting antibodies that inhibit receptor binding [69,70] . A second aspect of var gene specialization is that the expression of particular genes is associated with severe clinical forms of malaria in children [71–73] , probably due to variant pfEMP1 products causing infected erythrocyte cytoadhesion to particular capillary endothelial surfaces [74,75] or enhanced rosetting of uninfected erythrocytes around infected erythrocytes [76] .…”

Section: Evidence To Prioritize Candidate Antigensmentioning

confidence: 99%

Paths to a malaria vaccine illuminated by parasite genomics

Conway

2015

Trends in Genetics

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“…A homologous sequence (PxRRxxxC) present in DBL4ε domain is contained in 6593 (not used for immunisations) (Figure 1A) and a shorter PxRRxxLx sequence was found in DBL6ε N-terminus in some strains [28], confirming this motif’s presence in nearly all DBL domains [5].…”

Section: Resultsmentioning

confidence: 71%

“…Completely 3 10 -helix structure 6622 ( 2464 K KWWDMNKYHIWESML 2479 ) determined by 1 H-NMR (Figure 4F, grey ribbon) is localised in VB4; partially α-helical 6621 ( 2446 SDKIGKILGDGVGQ N 2460 EKR 2463 ) (Figure 4F, red ribbon) localised in one of the elbows of DBL6ε domains, in VB4 [28], [36], established a H-bond between N2460 O (6621) and K2464 HN (6622), forming a niche for a non-identified RBC receptor binding (Figure 4G). …”

Section: Resultsmentioning

confidence: 99%

Using the PfEMP1 Head Structure Binding Motif to Deal a Blow at Severe Malaria

et al. 2014

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Plasmodium falciparum (Pf) malaria causes 200 million cases worldwide, 8 million being severe and complicated leading to ∼1 million deaths and ∼100,000 abortions annually. Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) has been implicated in cytoadherence and infected erythrocyte rosette formation, associated with cerebral malaria; chondroitin sulphate-A attachment and infected erythrocyte sequestration related to pregnancy-associated malaria and other severe forms of disease. An endothelial cell high activity binding peptide is described in several of this ∼300 kDa hypervariable protein’s domains displaying a conserved motif (GACxPxRRxxLC); it established H-bonds with other binding peptides to mediate red blood cell group A and chondroitin sulphate attachment. This motif (when properly modified) induced PfEMP1-specific strain-transcending, fully-protective immunity for the first time in experimental challenge in Aotus monkeys, opening the way forward for a long sought-after vaccine against severe malaria.

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Structural and Immunological Correlations between the Variable Blocks of the VAR2CSA Domain DBL6ε from Two Plasmodium falciparum Parasite Lines

Cited by 20 publications

References 47 publications

Multiplexing detection of IgG against Plasmodium falciparum pregnancy-specific antigens

Multiplexing detection of IgG against Plasmodium falciparum pregnancy-specific antigens

Paths to a malaria vaccine illuminated by parasite genomics

Using the PfEMP1 Head Structure Binding Motif to Deal a Blow at Severe Malaria

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