Structural patterns of selection and diversity for Plasmodium vivax antigens DBP and AMA1

Abstract

BackgroundPlasmodium vivax is a significant contributor to the global malaria burden, and a vaccine targeting vivax malaria is urgently needed. An understanding of the targets of functional immune responses during the course of natural infection will aid in the development of a vaccine. Antibodies play a key role in this process, with responses against particular epitopes leading to immune selection pressure on these epitopes. A number of techniques exist to estimate levels of immune selection pressure on particular epitopes, with a sliding window analysis often used to determine particular regions likely to be under immune pressure. However, such analysis neglects protein three-dimensional structural information. With this in mind, a newly developed tool, BioStructMap, was applied to two key antigens from Plasmodium vivax: PvAMA1 and PvDBP Region II. This tool incorporates structural information into tests of selection pressure.ResultsSequences from a number of populations were analysed, examining spatially-derived nucleotide diversity and Tajima’s D over protein structures for PvAMA1 and PvDBP. Structural patterns of nucleotide diversity were similar across all populations examined, with Domain I of PvAMA1 having the highest nucleotide diversity and displaying significant signatures of immune selection pressure (Tajima’s D > 0). Nucleotide diversity for PvDBP was highest bordering the dimerization and DARC-binding interface, although there was less evidence of immune selection pressure on PvDBP compared with PvAMA1. This study supports previous work that has identified Domain I as the main target of immune-mediated selection pressure for PvAMA1, and also supports studies that have identified functional epitopes within PvDBP Region II.ConclusionsThe BioStructMap tool was applied to leading vaccine candidates from P. vivax, to examine structural patterns of selection and diversity across a number of geographic populations. There were striking similarities in structural patterns of diversity across multiple populations. Furthermore, whilst regions of high diversity tended to surround conserved binding interfaces, a number of protein regions with very low diversity were also identified, and these may be useful targets for further vaccine development, given previous evidence of functional antibody responses against these regions.Electronic supplementary materialThe online version of this article (10.1186/s12936-018-2324-3) contains supplementary material, which is available to authorized users.

Plasmodium vivax AMA1: Implications of distinct haplotypes for immune response

“…In addition to being the most polymorphic domain [19,47,48] DI also contains the binding site to RON2, which acts in actin-myosin-associated moving junction formation. RON2 binds to a conserved portion of AMA1 [49] that is surrounded by highly polymorphic regions [50]. Therefore, DI is considered an important region for antibody response, while DII is considered to be the most immunogenic both in P. falciparum [51] and P. vivax [17].…”

Hotspots in Plasmodium and RBC Receptor-Ligand Interactions: Key Pieces for Inhibiting Malarial Parasite Invasion

“…Biophysical studies have shown that a non-sulfated DARC construct functionally binds to and is capable of inducing RII-DBP1 dimerization [ 44 ], suggesting that regions outside of the sulfotyrosine residues play an important role in binding interaction. Interestingly, it has been identified that DBP1 SD2 is characterized by having mainly polymorphic residues grouped around DARC dimerization and binding interphase in modeled RII-DBP1 structure [ 58 ]. It has been observed that nucleotide diversity within RII-DBP1 was universally highest in a region matching a previously identified inhibitory epitope (termed the DEK epitope) when examining nucleotide diversity patterns regarding individual geographical locations [ 50 ].…”

“…It has been observed that nucleotide diversity within RII-DBP1 was universally highest in a region matching a previously identified inhibitory epitope (termed the DEK epitope) when examining nucleotide diversity patterns regarding individual geographical locations [ 50 ]. SD3, located at the opposite end of SD1-SD2, had very low nucleotide diversity in all populations [ 58 ]. Attention must thus be paid to regions having low substitution rates which could reduce strain specificity.…”

“…It overlapped the whole HARPB 1639 sequence and the epitopes recognized by mAb 3C9 and 2C6 [ 50 , 56 ]. This hotspot (located in SD3 between residues 476–500) is a promising target considering that it contains regions specifically interacting with reticulocytes, mAbs targeting it can highly inhibit parasite entry to and interaction with reticulocytes, and has fewer polymorphic changes than SD2 [ 28 , 33 , 56 , 58 ]. It has been reported that Abs targeting epitopes in this subdomain can inhibit erythrocyte binding by different RII-DBP1 allele variants [ 55 ].…”

Avaliação da imunogenicidade de diferentes formas alélicas da proteí­na recombinante PvAMA-1expressa em <i>Pichia pastoris</i>: impacto da diversidade antigênica

“…Alguns antígenos da fase sanguínea assexuada (merozoítas) de P. vivax têm sido explorados como candidatos a vacina, sendo os principais os seguintes: MSP-1, AMA-1 e DBP (BABON et al, 2007;BARGIERI et al, 2008;BHARDWAJ et al, 2015;BITENCOURT et al, 2013;CRAWFORD et al, 2010;ELIAS et al, 2014;GUY et al, 2018;JIANG et al, 2013;MAIGA et al, 2013;ROCHA et al, 2017). Já na fase sanguínea sexuada os estudos envolvem os antígenos Pvs25, Pvs45, Pvs48 e Pvs230 (BLAGBOROUGH et al, 2016;TACHIBANA et al, 2012;VALLEJO et al, 2016).…”