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Frequent expansion of Plasmodium vivax Duffy Binding Protein in Ethiopia and its epidemiological significance.

ABSTRACT: Plasmodium vivax invasion of human erythrocytes depends on the Duffy Binding Protein (PvDBP) which interacts with the Duffy antigen. PvDBP copy number has been recently shown to vary between P. vivax isolates in Sub-Saharan Africa. However, the extent of PvDBP copy number variation, the type of PvDBP multiplications, as well as its significance across broad samples are still unclear. We determined the prevalence and type of PvDBP duplications, as well as PvDBP copy number variation among 178 Ethiopian P. vivax isolates using a PCR-based diagnostic method, a novel quantitative real-time PCR assay and whole genome sequencing. For the 145 symptomatic samples, PvDBP duplications were detected in 95 isolates, of which 81 had the Cambodian and 14 Malagasy-type PvDBP duplications. PvDBP varied from 1 to >4 copies. Isolates with multiple PvDBP copies were found to be higher in symptomatic than asymptomatic infections. For the 33 asymptomatic samples, PvDBP was detected with two copies in two of the isolates, and both were the Cambodian-type PvDBP duplication. PvDBP copy number in Duffy-negative heterozygotes was not significantly different from that in Duffy-positives, providing no support for the hypothesis that increased copy number is a specific association with Duffy-negativity, although the number of Duffy-negatives was small and further sampling is required to test this association thoroughly.

SUBMITTER: Lo E

PROVIDER: S-EPMC6756552 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Frequent expansion of Plasmodium vivax Duffy Binding Protein in Ethiopia and its epidemiological significance.

Lo Eugenia E Hostetler Jessica B JB Yewhalaw Delenasaw D Pearson Richard D RD Hamid Muzamil M A MMA Gunalan Karthigayan K Kepple Daniel D Ford Anthony A Janies Daniel A DA Rayner Julian C JC Miller Louis H LH Yan Guiyun G

PLoS neglected tropical diseases 20190911 9

Plasmodium vivax invasion of human erythrocytes depends on the Duffy Binding Protein (PvDBP) which interacts with the Duffy antigen. PvDBP copy number has been recently shown to vary between P. vivax isolates in Sub-Saharan Africa. However, the extent of PvDBP copy number variation, the type of PvDBP multiplications, as well as its significance across broad samples are still unclear. We determined the prevalence and type of PvDBP duplications, as well as PvDBP copy number variation among 178 Eth ...[more]

PMID: 31509523

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Project description:BackgroundPlasmodium vivax Duffy binding protein (PvDBP) is a merozoite surface protein located in the micronemes of P. vivax. The invasion of human reticulocytes by P. vivax merozoites depends on the parasite DBP binding domain engaging Duffy Antigen Receptor for Chemokine (DARC) on these red blood cells (RBCs). PvDBPII shows high genetic diversity which is a major challenge to its use in the development of a vaccine against vivax malaria.MethodsA cross-sectional study was conducted from February 2021 to September 2022 in five study sites across Ethiopia. A total of 58 blood samples confirmed positive for P. vivax by polymerase chain reaction (PCR) were included in the study to determine PvDBPII genetic diversity. PvDBPII were amplified using primers designed from reference sequence of P. vivax Sal I strain. Assembling of sequences was done using Geneious Prime version 2023.2.1. Alignment and phylogenetic tree constructions using MEGA version 10.1.1. Nucleotide diversity and haplotype diversity were analysed using DnaSP version 6.12.03, and haplotype network was generated with PopART version 1.7.ResultsThe mean age of the participants was 25 years, 5 (8.6%) participants were Duffy negatives. From the 58 PvDBPII sequences, seven haplotypes based on nucleotide differences at 8 positions were identified. Nucleotide diversity and haplotype diversity were 0.00267 ± 0.00023 and 0.731 ± 0.036, respectively. Among the five study sites, the highest numbers of haplotypes were identified in Arbaminch with six different haplotypes while only two haplotypes were identified in Gambella. The phylogenetic tree based on PvDBPII revealed that parasites of different study sites shared similar genetic clusters with few exceptions. Globally, a total of 39 haplotypes were identified from 223 PvDBPII sequences representing different geographical isolates obtained from NCBI archive. The nucleotide and haplotype diversity were 0.00373 and 0.845 ± 0.015, respectively. The haplotype prevalence ranged from 0.45% to 27.3%. Two haplotypes were shared among isolates from all geographical areas of the globe.ConclusionsPvDBPII of the Ethiopian P. vivax isolates showed low nucleotide but high haplotype diversity, this pattern of genetic variability suggests that the population may have undergone a recent expansion. Among the Ethiopian P. vivax isolates, almost half of the sequences were identical to the Sal-I reference sequence. However, there were unique haplotypes observed in the Ethiopian isolates, which does not share with isolates from other geographical areas. There were two haplotypes that were common among populations across the globe. Categorizing population haplotype frequency can help to determine common haplotypes for designing an effective blood-stage vaccine which will have a significant role for the control and elimination of P. vivax.

Project description:BackgroundDuffy Binding Protein (PvDBP) binding to the Duffy antigen receptor for chemokine (DARC) is essential for Plasmodium vivax invasion of human reticulocytes. PvDBP copy number variation (CNV) might increase parasite invasion and thus parasitemia. We examined the spatial distribution of PvDBP CNVs and DARC genotypes and their association with parasitemia in P. vivax endemic settings in Ethiopia.Methodology/principal findingsP. vivax isolates (n = 435) collected from five P. vivax endemic settings in Ethiopia were genotyped by amplifying the GATA1 transcription factor-binding site of the Duffy blood group and the CNV of PvDBP was quantified. Parasitemia was determined using 18S-based qPCR. The majority of participants were Duffy positive (96.8%, 421/435). Of the few Duffy negative individuals, most (n = 8) were detected from one site (Gondar). Multiple copies of PvDBP were detected in 83% (363/435) isolates with significant differences between sites (range 60%-94%). Both heterozygous (p = 0.005) and homozygous (p = 0.006) patients were more likely to have been infected by parasites with multiple PvDBP copies than Duffy negatives. Parasitemia was higher among the Duffy positives (median 17,218 parasites/µL; interquartile range [IQR] 2,895-104,489) than Duffy negatives (170; 78-24,132, p = 0.004) as well as in infections with 2 to 3 PvDBP copies (20,468; 3,649-110,632, p = 0.001) and more than 3 PvDBP copies (17,139; 2,831-95,946, p = 0.004) than single copy (5,673; 249-76,605).Conclusions/significanceA high proportion of P. vivax infection was observed in Duffy positives in this study, yet few Duffy negatives were found infected with P. vivax. The significant prevalence of multi-copy PvDBP observed among Ethiopian P. vivax isolates explains the high prevalence and parasitemia observed in clinical cases. This suggests that vivax malaria is a public health concern in the country where the Duffy positive population predominates. Investigating the relative contribution to the maintenance of the infectious reservoir of infections with different genotyping backgrounds (both host and parasite) might be required.

Project description:BackgroundThe Duffy-binding protein II of Plasmodium vivax (PvDBPII) has been considered as an attractive target for vaccine-mediated immunity despite a possible highly polymorphic nature. Among seven PvDBP domains, domain II has been shown to exhibit a high rate of nonsynonymous polymorphism, which has been suggested to be a potential immune (antibody binding) evasion mechanism. This study aimed to determine the extent of genetic polymorphisms and positive natural selection at domain II of the PvDBP gene among a sampling of Thai P. vivax isolates.MethodsThe PvDBPII gene was PCR amplified and the patterns of polymorphisms were characterized from 30 Thai P. vivax isolates using DNA cloning and sequencing. Phylogenetic analysis of the sequences and positive selection were done using DnaSP ver 4.0 and MEGA ver 4.0 packages.ResultsThis study demonstrated a high rate of nonsynonymous polymorphism. Using Sal I as the reference strain, a total of 30 point-mutations were observed in the PvDBPII gene among the set of Thai P. vivax isolates, of which 25 nonsynonymous and five synonymous were found. The highest frequency of polymorphism was found in five variant amino acids (residues D384G, R390H, L424I, W437R, I503K) with the variant L424I having the highest frequency. The difference between the rates of nonsynonymous and synonymous mutations estimated by the Nei and Gojobori's method suggested that PvDBPII antigen appears to be under selective pressure. Phylogenetic analysis of PvDBPII Thai P. vivax isolates to others found internationally demonstrated six distinct allele groups. Allele groups 4 and 6 were unique to Thailand.ConclusionPolymorphisms within PvDBPII indicated that Thai vivax malaria parasites are genetically diverse. Phylogenetic analysis of DNA sequences using the Neighbour-Joining method demonstrated that Thai isolates shared distinct alleles with P. vivax isolates from different geographical areas. The study reported here will be valuable for the development of PvDBPII-based malaria vaccine.

Dataset Information

Frequent expansion of Plasmodium vivax Duffy Binding Protein in Ethiopia and its epidemiological significance.

Publications

Frequent expansion of Plasmodium vivax Duffy Binding Protein in Ethiopia and its epidemiological significance.

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