Abstract
The RBSA protein is encoded by a gene described in Plasmodium species having tropism for reticulocytes. Since this protein is antigenic in natural infections and can bind to target cells, it has been proposed as a potential candidate for an anti-Plasmodium vivax vaccine. However, genetic diversity (a challenge which must be overcome for ensuring fully effective vaccine design) has not been described at this locus. Likewise, the minimum regions mediating specific parasite-host interaction have not been determined. This is why the rbsa gene’s evolutionary history is being here described, as well as the P. vivax rbsa (pvrbsa) genetic diversity and the specific regions mediating parasite adhesion to reticulocytes. Unlike what has previously been reported, rbsa was also present in several parasite species belonging to the monkey-malaria clade; paralogs were also found in Plasmodium parasites invading reticulocytes. The pvrbsa locus had less diversity than other merozoite surface proteins where natural selection and recombination were the main evolutionary forces involved in causing the observed polymorphism. The N-terminal end (PvRBSA-A) was conserved and under functional constraint; consequently, it was expressed as recombinant protein for binding assays. This protein fragment bound to reticulocytes whilst the C-terminus, included in recombinant PvRBSA-B (which was not under functional constraint), did not. Interestingly, two PvRBSA-A-derived peptides were able to inhibit protein binding to reticulocytes. Specific conserved and functionally important peptides within PvRBSA-A could thus be considered when designing a fully-effective vaccine against P. vivax.
Highlights
This study evaluated pvrbsa genetic diversity, assessed the evolutionary forces involved in causing the observed polymorphism and established minimum regions involved in protein–cell interaction
A contig was found in parsimony-informative sites (Ps). inui and P. fragile having higher than 60% identity whilst two different contigs were found in P. cynomolgi having 80% identity with Sal-I pvrbsa (Supplementary Data Sheet 1B)
The reticulocyte binding surface antigen (RBSA) protein has previously been identified as an antigen exclusive to Plasmodium species invading reticulocytes (Moreno-Perez et al, 2017), it is present in several monkey-malaria lineage species
Summary
Plasmodium vivax is a parasite which emerged in Asia (Escalante et al, 2005; Carlton et al, 2013) ( an African origin is likely, Liu et al, 2014), involving a host-switch from monkeys to humans (Mu et al, 2005) around 1.3–2.9 million years ago (Pacheco et al, 2011), Plasmodium cynomolgi being the most phylogenetically related species (Mu et al, 2005; Pacheco et al, 2011; Tachibana et al, 2012). P. vivax reached countries on the 5 continents through human migration (Rodrigues et al, 2018), currently predominating in Asia and America (Guerra et al, 2010; Gething et al, 2012) This species is considered the second most important human-malaria parasite worldwide, due to the morbidity it causes (WHO, 2017). New interventions must be designed which can reduce the parasite reservoir, limiting the time that a human (or mosquito) host is infectious (Barry and Arnott, 2014) This goal could be achieved by developing a fully effective antimalarial vaccine which, together with existing control measures, could contribute towards a malaria-free world (Barry and Arnott, 2014; White et al, 2014)
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