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. 2018 Oct 22;12(10):e0006555.
doi: 10.1371/journal.pntd.0006555. eCollection 2018 Oct.

Genetic diversity in two Plasmodium vivax protein ligands for reticulocyte invasion

Affiliations

Genetic diversity in two Plasmodium vivax protein ligands for reticulocyte invasion

Camille Roesch et al. PLoS Negl Trop Dis. .

Abstract

The interaction between Plasmodium vivax Duffy binding protein (PvDBP) and Duffy antigen receptor for chemokines (DARC) has been described as critical for the invasion of human reticulocytes, although increasing reports of P. vivax infections in Duffy-negative individuals questions its unique role. To investigate the genetic diversity of the two main protein ligands for reticulocyte invasion, PvDBP and P. vivax Erythrocyte Binding Protein (PvEBP), we analyzed 458 isolates collected in Cambodia and Madagascar from individuals genotyped as Duffy-positive. First, we observed a high proportion of isolates with multiple copies PvEBP from Madagascar (56%) where Duffy negative and positive individuals coexist compared to Cambodia (19%) where Duffy-negative population is virtually absent. Whether the gene amplification observed is responsible for alternate invasion pathways remains to be tested. Second, we found that the PvEBP gene was less diverse than PvDBP gene (12 vs. 33 alleles) but provided evidence for an excess of nonsynonymous mutations with the complete absence of synonymous mutations. This finding reveals that PvEBP is under strong diversifying selection, and confirms the importance of this protein ligand in the invasion process of the human reticulocytes and as a target of acquired immunity. These observations highlight how genomic changes in parasite ligands improve the fitness of P. vivax isolates in the face of immune pressure and receptor polymorphisms.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1
Distribution of PvDBP and PvEBP gene copy number in isolates from Cambodia and Madagascar (Panel A and B, left side). Number of isolates from Cambodia and Madagascar with single or multiple copies PvDBP and PvEBP genes (Panel A and B, right side). The grey squares represent the medians and whiskers the IQRs.
Fig 2
Fig 2
Distribution of PvDBP alleles observed in P. vivax isolates collected in Cambodia and Madagascar (Panel A). Phylogenetic tree inferred using the Neighbor-Joining method (Panel B). Each allele was numbered 1–32 (see S1 Table). The evolutionary distances were computed using the Poisson correction method [56] and are in the units of the number of amino acid substitutions per site. The analysis involved 33 amino acid sequences. Evolutionary analyses were conducted in MEGA7 [57].
Fig 3
Fig 3. Mapping of SNPs on the structure of PvDBPII (Protein Data Bank code 4NUU) monomer and PvEBPII.
SNPs present specifically to Cambodian and Madagascar isolates are highlighted in red and blue respectively, whereas SNPs present in the isolates from both the countries are highlighted in green. Putative binding residues on PvDBPII are highlighted in orange. Molecular surface diagram of PvDBPII is shown. SNPs and putative binding residues of PvDBPII are highlighted (Panel A). Predicted structure of PvEBPII is shown as molecular surface diagram and SNPs are highlighted (Panel B). Helical ribbon representation of PvDBPII (in light blue) and PvEBPII (in light grey) are superimposed. SNPs and putative binding residues are highlighted (Panel C).
Fig 4
Fig 4
Distribution of PvDBP gene copy number of 33 PvDBP alleles in isolates from Cambodia and Madagascar (Panel A). Distribution of PvEBP gene copy number of 12 PvEBP alleles in isolates from Cambodia and Madagascar (Panel B).
Fig 5
Fig 5
Distribution and number of PvEBP alleles among Malagasy and Cambodian samples (Panel A). Phylogenetic tree inferred using the Neighbor-Joining method (Panel B). Each allele was numbered 1–11 (see S2 Table). The evolutionary distances were computed using the Poisson correction method [56] and are in the units of the number of amino acid substitutions per site. The analysis involved 12 amino acid sequences. Evolutionary analyses were conducted in MEGA7 [57].

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