Abstract
BackgroundErythrocyte invasion by Plasmodium falciparum is a complex process that involves two families; Erythrocyte Binding-Like (EBL) and the Reticulocyte Binding-Like (PfRh) proteins. Antibodies that inhibit merozoite attachment and invasion are believed to be important in mediating naturally acquired immunity and immunity generated by parasite blood stage vaccine candidates. The hypotheses tested in this study were 1) that antibody responses against specific P. falciparum invasion ligands (EBL and PfRh) differ between symptomatic and asymptomatic individuals living in the low-transmission region of the Peruvian Amazon and 2), such antibody responses might have an association, either direct or indirect, with clinical immunity observed in asymptomatically parasitaemic individuals.MethodsELISA was used to assess antibody responses (IgG, IgG1 and IgG3) against recombinant P. falciparum invasion ligands of the EBL (EBA-175, EBA-181, EBA-140) and PfRh families (PfRh1, PfRh2a, PfRh2b, PfRh4 and PfRh5) in 45 individuals infected with P. falciparum from Peruvian Amazon. Individuals were classified as having symptomatic malaria (N=37) or asymptomatic infection (N=8).ResultsAntibody responses against both EBL and PfRh family proteins were significantly higher in asymptomatic compared to symptomatic individuals, demonstrating an association with clinical immunity. Significant differences in the total IgG responses were observed with EBA-175, EBA-181, PfRh2b, and MSP119 (as a control). IgG1 responses against EBA-181, PfRh2a and PfRh2b were significantly higher in the asymptomatic individuals. Total IgG antibody responses against PfRh1, PfRh2a, PfRh2b, PfRh5, EBA-175, EBA-181 and MSP119 proteins were negatively correlated with level of parasitaemia. IgG1 responses against EBA-181, PfRh2a and PfRh2b and IgG3 response for PfRh2a were also negatively correlated with parasitaemia.ConclusionsThese data suggest that falciparum malaria patients who develop clinical immunity (asymptomatic parasitaemia) in a low transmission setting such as the Peruvian Amazon have antibody responses to defined P. falciparum invasion ligand proteins higher than those found in symptomatic (non-immune) patients. While these findings will have to be confirmed by larger studies, these results are consistent with a potential role for one or more of these invasion ligands as a component of an anti-P. falciparum vaccine in low-transmission malaria-endemic regions.
Highlights
Erythrocyte invasion by Plasmodium falciparum is a complex process that involves two families; Erythrocyte Binding-Like (EBL) and the Reticulocyte Binding-Like (PfRh) proteins
Given the epidemiological observations indicating clinical immunity against P. falciparum, this study aimed to test the hypothesis that antibody responses against P. falciparum invasion ligands belonging to both Erythrocyte Binding-Like proteins (EBL) and Reticulocyte binding-like (PfRh) protein families might differ between symptomatic (Sym) and asymptomatic (Asy) individuals living in the low-transmission region of the Peruvian Amazon, and potentially contributing to explaining mechanisms of clinical immunity observed in the Asy individuals
Samples were tested against a comprehensive panel of known EBL and PfRh ligands except EBL-1; a majority of the Peruvian P. falciparum field isolates do not express EBL-1 as the gene in these parasites contained a fivethymidine insertion that results in premature translational termination and lack of protein expression [Lopez-Perez M et al, manuscript in preparation]
Summary
Erythrocyte invasion by Plasmodium falciparum is a complex process that involves two families; Erythrocyte Binding-Like (EBL) and the Reticulocyte Binding-Like (PfRh) proteins. The cytophilic IgG1 and IgG3 antibody isotype subclasses have been reported to be associated with protective responses generated against invasion ligands [4,5,6], by enabling the activation of complement and antibodydependent phagocytosis and parasite clearance [7]. It remains unclear which merozoite invasion ligand antigens might be the most important targets of naturally acquired clinical immunity, and whether the importance of such antigens are of regional specificity or globally relevance [2]
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