Genetic diversity of the Plasmodium vivax merozoite surface protein-5 locus from diverse geographic origins

Abstract

Plasmodium vivax merozoite surface protein-5 (PvMsp-5), a potential vaccine candidate, is encoded by a two-exon single copy gene. We have conducted a comprehensive analysis of PvMsp-5 by sequencing the entire gene of four parasite populations from northwestern Thailand (n = 73), southern Thailand (n = 53), Indonesia (n = 25) and Brazil (n = 24), and five isolates from other endemic areas. Results reveal that exon I exhibits a significantly higher level of nucleotide diversity at both synonymous and nonsynonymous sites than exon II (p < 0.01). Neutrality tests based on both intraspecific and interspecific nucleotide polymorphism have detected a signature of positive selection in exon I of all populations while substitutions in exon II mainly followed neutral expectation except that three residues in exon II of northwestern Thailand population appear to be positively selected using the Bayes Empirical Bayes method. Short imperfect repeats were identified in exon I at an equivalent region to its orthologue in P. knowlesi, supporting their close genetic relatedness. Significant levels of population subdivision were detected among most populations including those between northwestern and southern Thailand (p < 10−5), implying absent or minimal gene flow between these populations. Importantly, evidences for intragenic recombination in PvMsp-5 were found in most populations except that from southern Thailand in which haplotype diversity and nucleotide diversity were exceptionally low. Results from Fu and Li’s D*, F* and D and F tests suggested that PvMsp-5 of most P. vivax populations have been maintained by balancing selection whereas southern Thailand population could have gone through recent bottleneck events. These findings are concordant with a substantial reduction in number of P. vivax cases in southern Thailand during the past decade, followed by a very recent population expansion. Therefore, spatio-temporal monitoring of parasite population genetics provides important implications for disease control.

Evidence of purifying selection on merozoite surface protein 8 (MSP8) and 10 (MSP10) in Plasmodium spp.

“…Among all proteins involved in the invasion of the red blood cell, MSPs comprise some of the best characterized proteins in P. falciparum and some of them are considered promising vaccine candidates due to their accessibility to interaction with host immune system molecules (Richards and Beeson, 2009). Comparative evolutionary studies have shown that several of these proteins are important in the host-parasite interaction (Escalante et al, 2004; Weedall and Conway, 2010).…”

“…Immunization with blood-stage antigens has been shown to be protective in a number of animal models using different antigens. At present, the leading blood-stage vaccine candidates are all proteins expressed during the invasion of the red blood cells (RBCs), either contained within the apical organelles or located on the merozoite surface (Richards and Beeson, 2009, Alaro et al, 2010). However, one of the challenges in developing vaccines targeting these antigens is overcoming their genetic diversity.…”

Merozoite surface protein-3 alpha as a genetic marker for epidemiologic studies in Plasmodium vivax: a cautionary note

“…It is noteworthy, though, that despite it being significantly less than at synonymous sites, diversity at non-synonymous sites in both P. vivax ( dN  = 0.023 ± 0.003) and P. cynomolgi ( dN  = 0.058 ± 0.005) was substantial, with amino acid changes accordingly frequent. Intraspecies diversity for MSP-3α was comparable to that seen for other merozoite surface proteins, such as MSP-5 [59], and the 200 L fragment of MSP-1 [60], but was substantially higher than for those thought to be evolving under purifying selection such as MSP-7 [61], MSP-8, and MSP-10 [44]. …”

In silicoanalysis for structure, function and T-cell epitopes of a hypothetical conserved (HP-C) protein coded by PVX_092425 inPlasmodium vivax

“…16 Among them, 12 GPI-APs (PvMSP-1, PvMSP-4, PvMSP-5, PvMSP-8, PvMSP-10, Pv12, Pv34, Pv38, Pvs25, Pvs28, PvCSP and PvRAMA) have been characterized and some of them have been considered as potential vaccine candidates. [17][18][19][20][21][22][23][24][25] However, the other P. vivax GPI-APs including a hypothetical conserved (HP-C) protein named Pvx_092425 coded by gene PVX_092425 still remain uncharacterized and their precise role also stay unclear. To find novel vaccine candidates of P. vivax, the identification and characterization of new antigens among GPI-APs of P. vivax are considered to be one of the promising strategies.…”