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

Abstract

Evidence for natural selection, positive or negative, on gene encoding antigens may indicate variation or functional constraints that are immunologically relevant. Most malaria surface antigens with high genetic diversity have been reported to be under positive-diversifying selection. However, antigens with limited genetic variation are usually ignored in terms of the role that natural selection may have in generating such patterns. We investigated orthologous genes encoding two merozoite proteins, MSP8 and MSP10, among several mammalian Plasmodium spp. These antigens, together with MSP1, are among the few MSPs that have two epidermal growth factor-like domains (EGF) at the C-terminal. Those EGF are relatively conserved (low levels of genetic polymorphism) and have been proposed to act as ligands during the invasion of RBCs. We use several evolutionary genetic methods to detect patterns consistent with natural selection acting on MSP8 and MSP10 orthologs in the human parasites P. falciparum and P. vivax, as well as closely related malarial species found in non-human primates (NHPs). Overall, these antigens have low polymorphism in the human parasites in comparison with the orthologs from other Plasmodium species. We found that the MSP10 gene polymorphism in P. falciparum only harbor non-synonymous substitutions, a pattern consistent with a gene under positive selection. Evidence of purifying selection was found on the polymorphism observed in both orthologs from P. cynomolgi, a non-human primate parasite closely related to P. vivax, but it was not conclusive in the human parasite. Yet, using phylogenetic base approaches, we found evidence for purifying selection on both MSP8 and MSP10 in the lineage leading to P. vivax. Such antigens evolving under strong functional constraints could become valuable vaccine candidates. We discuss how comparative approaches could allow detecting patterns consistent with negative selection even when there is low polymorphism in the extant populations.

The evolution and diversity of a low complexity vaccine candidate, merozoite surface protein 9 (MSP-9), in Plasmodium vivax and closely related species

“…It is worth noting that it has been hypothesized that natural selection is less efficient when acting at the blood stage of P. vivax than P. falciparum (Schneider and Escalante 2013). Such predictions, together with the contrasting patterns observed in orthologous merozoite proteins such as MSP-1, MSP-10 (Pacheco et al 2007; 2012) and the one studied here; further reinforce the notion that the differences between P. falciparum and P. vivax need to be considered so findings in one species are not simply translated to the other.…”

“…Studying the role that natural selection may play in the absence of polymorphism is difficult simply because it could be the result of demographic processes such as population expansions after a bottleneck. This situation is not unique to MSP-9, other merozoite proteins such as merozoite surface protein-8 (MSP-8) and merozoite surface protein-10 (MSP-10) show very limited genetic polymorphism (Pacheco et al, 2012). Establishing whether such conserved parts of the protein are indeed under purifying selection is important since they may offer valuable targets for antimalarial vaccines if protective immune responses could be elicited against them (Baum et al, 2003; Cole-Tobian and King, 2003; Martinez et al, 2004; Pacheco et al, 2010; 2012).…”

A Chimeric Plasmodium falciparum Merozoite Surface Protein Vaccine Induces High Titers of Parasite Growth Inhibitory Antibodies

“…MSP8 is well conserved among the species of plasmodial parasites which infect a range of hosts, including rodents, nonhuman primates, and human subjects (16,17). Full-length P. falciparum MSP8 contains ϳ600 amino acids, slightly larger than its orthologs in other plasmodial species due to the presence of an asparagine and aspartic acid (Asn/Asp)-rich domain of ϳ170 amino acids near its N terminus.…”

Characterizing the genetic diversity of the monkey malaria parasite Plasmodium cynomolgi

“…This pattern in P. cynomolgi has been reported for several antigen genes, including circumsporozoite protein gene (CSP) (Pacheco et al ., 2012b), merozoite surface protein 1 (MSP1) (Tanabe et al ., 2007), MSP3 (Rice et al ., 2014), MSP8, and MSP10 (Pacheco et al ., 2012a), suggesting that the fact that the genetic differences shown by Berok and Gombak might be due to the geographical location or host variation. Further sampling of this widespread parasite of macaques is clearly needed to investigate in detail whether there is geographical population genetic structure in P. cynomolgi , and whether particular polymorphic genes are under selection.…”