Abstract
BackgroundRosetting is a Plasmodium falciparum virulence factor implicated in the pathogenesis of life-threatening malaria. Rosetting occurs when parasite–derived P. falciparum Erythrocyte Membrane Protein One (PfEMP1) on the surface of infected erythrocytes binds to human receptors on uninfected erythrocytes. PfEMP1 is a possible target for a vaccine to induce antibodies to inhibit rosetting and prevent severe malaria.Methodology/FindingsWe examined the vaccine potential of the six extracellular domains of a rosette-mediating PfEMP1 variant (ITvar9/R29var1 from the R29 parasite strain) by immunizing rabbits with recombinant proteins expressed in E. coli. Antibodies raised to each domain were tested for surface fluorescence with live infected erythrocytes, rosette inhibition and phagocytosis-induction. Antibodies to all PfEMP1 domains recognized the surface of live infected erythrocytes down to low concentrations (0.02–1.56 µg/ml of total IgG). Antibodies to all PfEMP1 domains except for the second Duffy-Binding-Like region inhibited rosetting (50% inhibitory concentration 0.04–4 µg/ml) and were able to opsonize and induce phagocytosis of infected erythrocytes at low concentrations (1.56–6.25 µg/ml). Antibodies to the N-terminal region (NTS-DBL1α) were the most effective in all assays. All antibodies were specific for the R29 parasite strain, and showed no functional activity against five other rosetting strains.Conclusions/SignificanceThese results are encouraging for vaccine development as they show that potent antibodies can be generated to recombinant PfEMP1 domains that will inhibit rosetting and induce phagocytosis of infected erythrocytes. However, further work is needed on rosetting mechanisms and cross-reactivity in field isolates to define a set of PfEMP1 variants that could induce functional antibodies against a broad range of P. falciparum rosetting parasites.
Highlights
The global mortality from malaria continues to be a huge problem, with Plasmodium falciparum being the major cause of severe, life-threatening malaria in African children [1]
Addition of the short N-terminal sequence (NTS) to DBL1a resulted in production of soluble protein, suggesting that the NTS may be an integral part of the DBL1a domain
Two previous studies have shown that antibodies to DBL1a are able to inhibit rosetting [17,24], little is known about the effect of antibodies against the other extracellular domains of rosette-mediating P. falciparum Erythrocyte Membrane Protein-1 (PfEMP1) variants
Summary
The global mortality from malaria continues to be a huge problem, with Plasmodium falciparum being the major cause of severe, life-threatening malaria in African children [1]. Results from human genetic studies have shown that erythrocyte polymorphisms that reduce rosetting (complement receptor 1 deficiency [9] and blood group O [5]), confer protection against severe malaria, reducing the odds ratio for severe disease by about two thirds [10,11]. Therapeutic interventions that target rosetting may have potential to decrease the global burden of severe malaria [14,15] This is further supported by the observation that rosette-inhibiting antibody responses are associated with protection from severe malaria [2]. PfEMP1 is a possible target for a vaccine to induce antibodies to inhibit rosetting and prevent severe malaria
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