Genetic diversity in two<i>Plasmodium vivax</i>protein ligands for reticulocyte invasion

Roesch, Camille; Popovici, Jean; Bin, Sophalai; Run, Vorleak; Kim, Saorin; Ramboarina, Stephanié; Rakotomalala, Emma; Rakotoarison, Rado; Rasoloharimanana, Tsikiniaina L; Andriamanantena, Zo; Kumar, Anuj; Guillotte-Blisnick, Micheline; Huon, Christèle; Serre, David; Chitnis, Chetan E.; Vigan-Womas, Inès; Ménard, Didier

doi:10.1101/328757

Cited by 12 publications

(18 citation statements)

References 55 publications

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“…We evaluated how the PvDBP sequence polymorphism of the isolates used in the invasion assays affected the response of the parasites to the humabs in order to assess if antigenic variation was responsible for the variations in inhibition observed. Among the 29 isolates used for the in vitro invasion assays, we observed 20 different alleles of DBPII none of which being the Sal1 reference allele, reflecting the known diversity of this gene (Supplementary Table 1) 23 . pvdbp amplification was observed in six of those alleles confirming that this gene amplification is not restricted to a particular parasite genotype ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Yet some individuals with high titers of these naturally acquired antibodies remain susceptible to malaria infection and disease suggesting alternative mechanisms to antigenic diversity that the parasite might have evolved to escape this strain-transcending immunity. Recently it was shown that some Pv parasites had two or more copies of the gene coding for PvDBP [21][22][23] . Such Pv isolates were identified from many endemic areas around the world.…”

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confidence: 99%

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Amplification of Duffy binding protein-encoding gene allows Plasmodium vivax to evade host anti-DBP humoral immunity

et al. 2020

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Antigenic variation, the capacity to produce a range of variable antigens, is a well-described strategy of Plasmodium and other parasites to evade host immunity. Here, we show that gene amplification is an additional evasion mechanism used by Plasmodium vivax to escape humoral immunity targeting PvDBP, the key ligand involved in reticulocyte invasion. PvDBP gene amplification leads to increased mRNA levels and protects P. vivax in vitro against invasion inhibitory human monoclonal antibodies targeting a conserved binding domain of DBP. Patient samples suggest that parasites with increased pvdbp copy number are able to infect individuals with naturally acquired antibodies highly blocking the binding of PvDBP to the Duffy receptor. These results show that gene copy number variation affect the parasite's ability to evade anti-PvDBP humoral immunity.

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Section: Resultsmentioning

confidence: 99%

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Amplification of Duffy binding protein-encoding gene allows Plasmodium vivax to evade host anti-DBP humoral immunity

et al. 2020

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“…Although the significance of the expansion of DBP1 is unclear, it suggests the possibility that parasites expressing high levels of DBP1 could infect Duffy-negative erythrocytes expressing a low level of Duffy antigen (leaky expression) in these cells. Alternatively, P. vivax may have evolved to use other invasion pathways relying on ligands other than DBP1 (22,26,27). P. vivax infections in Duffy-positive individuals are generally benign.…”

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Transcriptome profiling ofPlasmodium vivaxinSaimirimonkeys identifies potential ligands for invasion

Gunalan

Sá

Barros

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Unlike the case in Asia and Latin America,Plasmodium vivaxinfections are rare in sub-Saharan Africa due to the absence of the Duffy blood group antigen (Duffy antigen), the only known erythrocyte receptor for theP. vivaxmerozoite invasion ligand, Duffy binding protein 1 (DBP1). However,P. vivaxinfections have been documented in Duffy-negative individuals throughout Africa, suggesting thatP. vivaxmay use ligands other than DBP1 to invade Duffy-negative erythrocytes through other receptors. To identify potentialP. vivaxligands, we compared parasite gene expression inSaimiriandAotusmonkey erythrocytes infected withP. vivaxSalvador I (Sal I). DBP1 bindsAotusbut does not bind toSaimirierythrocytes; thus,P. vivaxSal I must invadeSaimirierythrocytes independent of DBP1. Comparing RNA sequencing (RNAseq) data for late-stage infections inSaimiriandAotuserythrocytes when invasion ligands are expressed, we identified genes that belong to tryptophan-rich antigen and merozoite surface protein 3 (MSP3) families that were more abundantly expressed inSaimiriinfections compared withAotusinfections. These genes may encode potential ligands responsible forP. vivaxinfections of Duffy-negative Africans.

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“…While we did not detect any formal association between PvDBP copy number and Duffy negativity, it is worth noting that in other parts of the world such as Cambodia, India, and Brazil where only a small proportion of Duffy-negative individuals live, PvDBP expansion was observed with much lower frequency [24]. Although the PvEBP gene was shown to be variable in copy number among the Malagasy P. vivax [42], we detected only a single copy in the Ethiopian P. vivax samples based on whole genome sequences. The functional significance of PvDBP expansion merits further investigations through comparison of gene expression patterns and in-vitro binding assay of varying PvDBP dosage, and study of P. vivax isolates from Duffy negative individuals is clearly a high priority.…”

Section: Discussionmentioning

confidence: 97%

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

Hostetler

Yewhalaw

et al. 2019

Preprint

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28 Plasmodium vivax invasion of human erythrocytes depends on the Duffy Binding 29 Protein (PvDBP) which interacts with the Duffy antigen. PvDBP copy number varies 30 between P. vivax isolates, but the prevalence of PvDBP multiplications in Sub-Saharan 31 Africa and its impact are unknown. We determined the prevalence and type of PvDBP 32 duplications, as well as PvDBP copy number variation among 178 Ethiopian P. vivax 33 isolates using a PCR-based diagnostic method, a novel quantitative real-time PCR 34 assay and whole genome sequencing. For the 145 symptomatic samples, PvDBP 35 duplications were detected in 95 isolates, of which 81 had the Cambodian and 14 36 Malagasy-type PvDBP duplications. PvDBP varied from 1 to >4 copies. Isolates with 37 multiple PvDBP copies were found to be higher in symptomatic than asymptomatic 38 infections. For the 33 asymptomatic samples, PvDBP was detected with two copies in 39 two of the isolates, and both were the Cambodian-type PvDBP duplication. PvDBP copy 40 number in Duffy-negative heterozygotes was not significantly different from that in 41 Duffy-positives, providing no support for the hypothesis that increased copy number is a 42 specific association with Duffy-negativity, although the number of Duffy-negatives was 43 small and further sampling is required to test this association thoroughly. 44 45 46 3 47 Author summary 48 Plasmodium vivax invasion of human erythrocytes relies on interaction between the 49 Duffy antigen and P. vivax Duffy Binding Protein (PvDBP). Whole genome sequences 50 from P. vivax field isolates in Madagascar identified a duplication of the PvDBP gene 51 and PvDBP duplication has also been detected in non-African P. vivax-endemic 52 countries. Two types of PvDBP duplications have been reported, termed Cambodian 53 and Malagasy-type duplications. Our study used a combination of PCR-based 54 diagnostic method, a novel quantitative real-time PCR assay, and whole genome 55 sequencing to determine the prevalence and type of PvDBP duplications, as well as 56 PvDBP copy number on a broad number of P. vivax samples in Ethiopia. We found that 57 over 65% of P. vivax isolated from the symptomatic infections were detected with 58 PvDBP duplications and PvDBP varied from 1 to >4 copies. The majority of PvDBP 59 duplications belongs to the Cambodian-type while the Malagasy-type duplications was 60 also detected. For the asymptomatic infections, despite a small sample size, the 61 majority of P. vivax were detected with a single-copy based on both PCR and qPCR 62 assays. There was no significant difference in PvDBP copy number between Duffy-null 63 heterozygote and Duffy-positive homozygote/heterozygote. Further investigation is 64 needed with expanded Duffy-null homozygotes to examine the functional significance of 65 PvDBP expansion.66 67 68 69 4 70 Introduction 71 Plasmodium vivax and P. falciparum are the two major parasite species that cause 72 clinical malaria worldwide. While P. falciparum causes most malaria mortality, P. vivax 73 can also cause severe dis...

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Genetic diversity in twoPlasmodium vivaxprotein ligands for reticulocyte invasion

Cited by 12 publications

References 55 publications

Amplification of Duffy binding protein-encoding gene allows Plasmodium vivax to evade host anti-DBP humoral immunity

Amplification of Duffy binding protein-encoding gene allows Plasmodium vivax to evade host anti-DBP humoral immunity

Transcriptome profiling ofPlasmodium vivaxinSaimirimonkeys identifies potential ligands for invasion

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

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