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Low levels of polymorphisms and no evidence for diversifying selection on the Plasmodium knowlesi Apical Membrane Antigen 1 gene.

Faber BW, Abdul Kadir K, Rodriguez-Garcia R, Remarque EJ, Saul FA, Vulliez-Le Normand B, Bentley GA, Kocken CH, Singh B - PLoS ONE (2015)

Bottom Line: Statistically significant differences in the quantity of three of the six high frequency mutations were observed between the two regions.These analyses suggest that the pkama1 gene is not under balancing selection, as observed for pfama1 and pvama1, and that the PkAMA1 protein is not a primary target for protective humoral immune responses in their reservoir macaque hosts, unlike PfAMA1 and PvAMA1 in humans.The low level of polymorphism justifies the development of a single allele PkAMA1-based vaccine.

View Article: PubMed Central - PubMed

Affiliation: Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, The Netherlands.

ABSTRACT
Infection with Plasmodium knowlesi, a zoonotic primate malaria, is a growing human health problem in Southeast Asia. P. knowlesi is being used in malaria vaccine studies, and a number of proteins are being considered as candidate malaria vaccine antigens, including the Apical Membrane Antigen 1 (AMA1). In order to determine genetic diversity of the ama1 gene and to identify epitopes of AMA1 under strongest immune selection, the ama1 gene of 52 P. knowlesi isolates derived from human infections was sequenced. Sequence analysis of isolates from two geographically isolated regions in Sarawak showed that polymorphism in the protein is low compared to that of AMA1 of the major human malaria parasites, P. falciparum and P. vivax. Although the number of haplotypes was 27, the frequency of mutations at the majority of the polymorphic positions was low, and only six positions had a variance frequency higher than 10%. Only two positions had more than one alternative amino acid. Interestingly, three of the high-frequency polymorphic sites correspond to invariant sites in PfAMA1 or PvAMA1. Statistically significant differences in the quantity of three of the six high frequency mutations were observed between the two regions. These analyses suggest that the pkama1 gene is not under balancing selection, as observed for pfama1 and pvama1, and that the PkAMA1 protein is not a primary target for protective humoral immune responses in their reservoir macaque hosts, unlike PfAMA1 and PvAMA1 in humans. The low level of polymorphism justifies the development of a single allele PkAMA1-based vaccine.

No MeSH data available.


Related in: MedlinePlus

Three-dimensional distribution of polymorphic amino acid residues of PkAMA1, PfAMA1 and PvAMA1.Two views of a surface representation, rotated by 180° with respect to each other, are shown for the crystal structures of (A) PkAMA1 (PDB entry 4UV6), (B) PfAMA1 (PDB entry 2Z8V) and (C) PvAMA1 (PDB entry 1W8L), with each orthologue oriented at equivalent angles. PkAMA1 polymorphisms are from this study, PfAMA1 polymorphisms are from refs [23,24] and PvAMA1 polymorphisms are from ref [25]. Polymorphic residues are labeled and colored in red for high frequency polymorphisms (> 10%) and in blue for low frequency polymorphisms (< 10%). Domains 1 and 2 from crystal structures of all three orthologues are shown in white. Domain 3, shown in grey, was modeled for PkAMA1 and PfAMA1 from the crystal structure of PvAMA1 since the crystal structure of this domain has not been determined for these two orthologues. (PkAMA1 Domain 3 polymorphic residues 411 and 481 are not shown as these are disordered and thus not visible in the PvAMA1 structure).
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pone.0124400.g003: Three-dimensional distribution of polymorphic amino acid residues of PkAMA1, PfAMA1 and PvAMA1.Two views of a surface representation, rotated by 180° with respect to each other, are shown for the crystal structures of (A) PkAMA1 (PDB entry 4UV6), (B) PfAMA1 (PDB entry 2Z8V) and (C) PvAMA1 (PDB entry 1W8L), with each orthologue oriented at equivalent angles. PkAMA1 polymorphisms are from this study, PfAMA1 polymorphisms are from refs [23,24] and PvAMA1 polymorphisms are from ref [25]. Polymorphic residues are labeled and colored in red for high frequency polymorphisms (> 10%) and in blue for low frequency polymorphisms (< 10%). Domains 1 and 2 from crystal structures of all three orthologues are shown in white. Domain 3, shown in grey, was modeled for PkAMA1 and PfAMA1 from the crystal structure of PvAMA1 since the crystal structure of this domain has not been determined for these two orthologues. (PkAMA1 Domain 3 polymorphic residues 411 and 481 are not shown as these are disordered and thus not visible in the PvAMA1 structure).

Mentions: Fig 3 shows the high and low frequency polymorphic amino acid residues on the PkAMA1 crystal structure [20] and compares them with those of PvAMA1 and PfAMA1. From these three-dimensional views, the differences between the proteins are clear: both PvAMA1 and PfAMA1 have more high-frequency polymorphic residues on the ectodomain of the protein, and while PvAMA1 has more polymorphic positions on the ectodomain compared to PkAMA1, PfAMA1 polymorphisms outnumber both of them by a significantly large margin. Note that the high-frequency residues preferentially locate to one face of the protein [22].


Low levels of polymorphisms and no evidence for diversifying selection on the Plasmodium knowlesi Apical Membrane Antigen 1 gene.

Faber BW, Abdul Kadir K, Rodriguez-Garcia R, Remarque EJ, Saul FA, Vulliez-Le Normand B, Bentley GA, Kocken CH, Singh B - PLoS ONE (2015)

Three-dimensional distribution of polymorphic amino acid residues of PkAMA1, PfAMA1 and PvAMA1.Two views of a surface representation, rotated by 180° with respect to each other, are shown for the crystal structures of (A) PkAMA1 (PDB entry 4UV6), (B) PfAMA1 (PDB entry 2Z8V) and (C) PvAMA1 (PDB entry 1W8L), with each orthologue oriented at equivalent angles. PkAMA1 polymorphisms are from this study, PfAMA1 polymorphisms are from refs [23,24] and PvAMA1 polymorphisms are from ref [25]. Polymorphic residues are labeled and colored in red for high frequency polymorphisms (> 10%) and in blue for low frequency polymorphisms (< 10%). Domains 1 and 2 from crystal structures of all three orthologues are shown in white. Domain 3, shown in grey, was modeled for PkAMA1 and PfAMA1 from the crystal structure of PvAMA1 since the crystal structure of this domain has not been determined for these two orthologues. (PkAMA1 Domain 3 polymorphic residues 411 and 481 are not shown as these are disordered and thus not visible in the PvAMA1 structure).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4400157&req=5

pone.0124400.g003: Three-dimensional distribution of polymorphic amino acid residues of PkAMA1, PfAMA1 and PvAMA1.Two views of a surface representation, rotated by 180° with respect to each other, are shown for the crystal structures of (A) PkAMA1 (PDB entry 4UV6), (B) PfAMA1 (PDB entry 2Z8V) and (C) PvAMA1 (PDB entry 1W8L), with each orthologue oriented at equivalent angles. PkAMA1 polymorphisms are from this study, PfAMA1 polymorphisms are from refs [23,24] and PvAMA1 polymorphisms are from ref [25]. Polymorphic residues are labeled and colored in red for high frequency polymorphisms (> 10%) and in blue for low frequency polymorphisms (< 10%). Domains 1 and 2 from crystal structures of all three orthologues are shown in white. Domain 3, shown in grey, was modeled for PkAMA1 and PfAMA1 from the crystal structure of PvAMA1 since the crystal structure of this domain has not been determined for these two orthologues. (PkAMA1 Domain 3 polymorphic residues 411 and 481 are not shown as these are disordered and thus not visible in the PvAMA1 structure).
Mentions: Fig 3 shows the high and low frequency polymorphic amino acid residues on the PkAMA1 crystal structure [20] and compares them with those of PvAMA1 and PfAMA1. From these three-dimensional views, the differences between the proteins are clear: both PvAMA1 and PfAMA1 have more high-frequency polymorphic residues on the ectodomain of the protein, and while PvAMA1 has more polymorphic positions on the ectodomain compared to PkAMA1, PfAMA1 polymorphisms outnumber both of them by a significantly large margin. Note that the high-frequency residues preferentially locate to one face of the protein [22].

Bottom Line: Statistically significant differences in the quantity of three of the six high frequency mutations were observed between the two regions.These analyses suggest that the pkama1 gene is not under balancing selection, as observed for pfama1 and pvama1, and that the PkAMA1 protein is not a primary target for protective humoral immune responses in their reservoir macaque hosts, unlike PfAMA1 and PvAMA1 in humans.The low level of polymorphism justifies the development of a single allele PkAMA1-based vaccine.

View Article: PubMed Central - PubMed

Affiliation: Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, The Netherlands.

ABSTRACT
Infection with Plasmodium knowlesi, a zoonotic primate malaria, is a growing human health problem in Southeast Asia. P. knowlesi is being used in malaria vaccine studies, and a number of proteins are being considered as candidate malaria vaccine antigens, including the Apical Membrane Antigen 1 (AMA1). In order to determine genetic diversity of the ama1 gene and to identify epitopes of AMA1 under strongest immune selection, the ama1 gene of 52 P. knowlesi isolates derived from human infections was sequenced. Sequence analysis of isolates from two geographically isolated regions in Sarawak showed that polymorphism in the protein is low compared to that of AMA1 of the major human malaria parasites, P. falciparum and P. vivax. Although the number of haplotypes was 27, the frequency of mutations at the majority of the polymorphic positions was low, and only six positions had a variance frequency higher than 10%. Only two positions had more than one alternative amino acid. Interestingly, three of the high-frequency polymorphic sites correspond to invariant sites in PfAMA1 or PvAMA1. Statistically significant differences in the quantity of three of the six high frequency mutations were observed between the two regions. These analyses suggest that the pkama1 gene is not under balancing selection, as observed for pfama1 and pvama1, and that the PkAMA1 protein is not a primary target for protective humoral immune responses in their reservoir macaque hosts, unlike PfAMA1 and PvAMA1 in humans. The low level of polymorphism justifies the development of a single allele PkAMA1-based vaccine.

No MeSH data available.


Related in: MedlinePlus