scholarly journals Genetic diversity in two Plasmodium vivax protein ligands for reticulocyte invasion

2018 ◽  
Author(s):  
Camille Roesch ◽  
Jean Popovici ◽  
Sophalai Bin ◽  
Vorleak Run ◽  
Saorin Kim ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Plasmodium Vivax ◽  
Binding Protein ◽  
Invasion Pathways ◽  
Genomic Changes ◽  
Synonymous Mutations ◽  
Protein Ligands ◽  
Immune Pressure ◽  
Erythrocyte Binding ◽  
Duffy Negative

AbstractThe 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. 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.

scholarly journals Genetic diversity and neutral selection in Plasmodium vivax erythrocyte binding protein correlates with patient antigenicity

2020 ◽  
Vol 14 (7) ◽  
pp. e0008202 ◽  
Author(s):  
Jin-Hee Han ◽  
Jee-Sun Cho ◽  
Jessica J. Y. Ong ◽  
Ji-Hoon Park ◽  
Myat Htut Nyunt ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Plasmodium Vivax ◽  
Binding Protein ◽  
Neutral Selection ◽  
Erythrocyte Binding

scholarly journals A Novel Erythrocyte Binding Protein of Plasmodium vivax Suggests an Alternate Invasion Pathway into Duffy-Positive Reticulocytes

mBio ◽  
2016 ◽  
Vol 7 (4) ◽  
Author(s):  
Francis B. Ntumngia ◽  
Richard Thomson-Luque ◽  
Letícia de Menezes Torres ◽  
Karthigayan Gunalan ◽  
Luzia H. Carvalho ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
Blood Group ◽  
Binding Protein ◽  
Antigen Receptor ◽  
Blood Stage ◽  
Duffy Binding Protein ◽  
Duffy Blood Group ◽  
Erythrocyte Binding ◽  
Invasion Pathway ◽  
Duffy Negative

ABSTRACT Erythrocyte invasion by malaria parasites is essential for blood-stage development and an important determinant of host range. In Plasmodium vivax , the interaction between the Duffy binding protein (DBP) and its cognate receptor, the Duffy antigen receptor for chemokines (DARC), on human erythrocytes is central to blood-stage infection. Contrary to this established pathway of invasion, there is growing evidence of P. vivax infections occurring in Duffy blood group-negative individuals, suggesting that the parasite might have gained an alternative pathway to infect this group of individuals. Supporting this concept, a second distinct erythrocyte binding protein (EBP2), representing a new member of the DBP family, was discovered in P. vivax and may be the ligand in an alternate invasion pathway. Our study characterizes this novel ligand and determines its potential role in reticulocyte invasion by P. vivax merozoites . EBP2 binds preferentially to young (CD71 high ) Duffy-positive (Fy + ) reticulocytes and has minimal binding capacity for Duffy-negative reticulocytes. Importantly, EBP2 is antigenically distinct from DBP and cannot be functionally inhibited by anti-DBP antibodies. Consequently, our results do not support EBP2 as a ligand for invasion of Duffy-negative blood cells, but instead, EBP2 may represent a novel ligand for an alternate invasion pathway of Duffy-positive reticulocytes. IMPORTANCE For decades, P. vivax infections in humans have been defined by a unique requirement for the interaction between the Duffy binding protein ligand of the parasite and the Duffy blood group antigen receptor (DARC). Recent reports of P. vivax infections in Duffy-negative individuals challenge this paradigm and suggest an alternate pathway of infection, potentially using the recently discovered EBP2. However, we demonstrate that EBP2 host cell specificity is more restricted than DBP binding and that EBP2 binds preferentially to Duffy-positive, young reticulocytes. This finding indicates that this DBP paralog does mediate a Duffy-independent pathway of infection.

scholarly journals Whole Genome Sequencing of Plasmodium vivax Isolates Reveals Frequent Sequence and Structural Polymorphisms in Erythrocyte Binding Genes

2020 ◽  
Author(s):  
Anthony Ford ◽  
Daniel Kepple ◽  
Beka Raya Abagero ◽  
Jordan Connors ◽  
Richard Pearson ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
Copy Number ◽  
Binding Protein ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Whole Genome ◽  
Single Nucleotide ◽  
Geographical Scale ◽  
Erythrocyte Binding ◽  
Duffy Negative

AbstractPlasmodium vivax malaria is much less common in Africa than the rest of the world because the parasite relies primarily on the Duffy antigen/chemokine receptor (DARC) to invade human erythrocytes, and the majority of Africans are Duffy negative. Recently, there has been a dramatic increase in the reporting of P. vivax cases in Africa, with a high number of them being in Duffy negative individuals, potentially indicating P. vivax has evolved an alternative invasion mechanism that can overcome Duffy negativity. Here, we analyzed single nucleotide polymorphism (SNP) and copy number variation (CNV) in Whole Genome Sequence (WGS) data from 44 P. vivax samples isolated from symptomatic malaria patients in southwestern Ethiopia, where both Duffy positive and Duffy negative individuals are found. A total of 236,351 SNPs were detected, of which 21.9% was nonsynonymous and 78.1% was synonymous mutations. The largest number of SNPs were detected on chromosomes 9 (33,478 SNPs; 14% of total) and 10 (28,133 SNPs; 11.9%). There were particularly high levels of polymorphism in erythrocyte binding gene candidates including reticulocyte binding protein 2c (RBP2c), merozoite surface protein 1 (MSP1), and merozoite surface protein 3 (MSP3.5, MSP3.85 and MSP3.9). Thirteen genes related to immunogenicity and erythrocyte binding function were detected with significant signals of positive selection. Variation in gene copy number was also concentrated in genes involved in host-parasite interactions, including the expansion of the Duffy binding protein gene (PvDBP) on chromosome 6 and several PIR genes. Based on the phylogeny constructed from the whole genome sequences, the expansion of these genes was an independent process among the P. vivax lineages in Ethiopia. We further inferred transmission patterns of P. vivax infections among study sites and showed various levels of gene flow at a small geographical scale. The genomic features of P. vivax provided baseline data for future comparison with those in Duffy-negative individuals, and allowed us to develop a panel of informative Single Nucleotide Polymorphic markers diagnostic at a micro-geographical scale.

scholarly journals Genetic Diversity and Natural Selection of Plasmodium vivax Duffy Binding Protein-II From China-Myanmar Border of Yunnan Province, China

2021 ◽  
Vol 12 ◽  
Author(s):  
Tian-Qi Shi ◽  
Hai-Mo Shen ◽  
Shen-Bo Chen ◽  
Kokouvi Kassegne ◽  
Yan-Bing Cui ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Population Structure ◽  
Natural Selection ◽  
Genetic Differentiation ◽  
Positive Selection ◽  
Plasmodium Vivax ◽  
Yunnan Province ◽  
Duffy Binding Protein ◽  
Synonymous Mutations ◽  
Selection Of

Malaria incidence has declined dramatically over the past decade and China was certified malaria-free in 2021. However, the presence of malaria in border areas and the importation of cases of malaria parasites are major challenges for the consolidation of the achievements made by China. Plasmodium vivax Duffy binding protein (PvDBP) performs a significant role in erythrocyte invasion, and is considered a promising P. vivax vaccine. However, the highly polymorphic region of PvDBP (PvDBP-II) impedes the development of blood-stage vaccine against P. vivax. In this study, we investigated the genetic diversity and natural selection of PvDBP-II among 124 P. vivax isolates collected from the China-Myanmar border (CMB) in Yunnan Province, China, during 2009–2011. To compare genetic diversity, natural selection, and population structure with CMB isolates, 85 pvdbp-II sequences of eastern Myanmar isolates were obtained from GenBank. In addition, global sequences of pvdbp-II were retrieved from GenBank to establish genetic differentiation relationships and networks with the CMB isolates. In total, 22 single nucleotide polymorphisms reflected in 20 non-synonymous and two synonymous mutations were identified. The overall nucleotide diversity of PvDBP-II from the 124 CMB isolates was 0.0059 with 21 haplotypes identified (Hd = 0.91). The high ratio of non-synonymous to synonymous mutations suggests that PvDBP-II had evolved under positive selection. Population structure analysis of the CMB and eastern Myanmar isolates were optimally grouped into five sub-populations (K = 5). Polymorphisms of PvDBP-II display that CMB isolates were genetically diverse. Mutation, recombination, and positive selection promote polymorphism of PvDBP-II of P. vivax population. Although low-level genetic differentiation in eastern Myanmar was identified along with the more effective malaria control measures, the complexity of population structure in malaria parasites has maintained. In conclusion, findings from this study advance knowledge of the understanding of the dynamic of P. vivax population, which will contribute to guiding the rational design of a PvDBP-II based vaccine.

scholarly journals Single-Chain Antibody Fragment Specific for Plasmodium vivax Duffy Binding Protein

2007 ◽  
Vol 14 (6) ◽  
pp. 726-731 ◽  
Author(s):  
So-Hee Kim ◽  
Seung-Young Hwang ◽  
Yong-Seok Lee ◽  
In-Hak Choi ◽  
Sae-Gwang Park ◽  
...  
Keyword(s):  
Phage Display ◽  
Plasmodium Vivax ◽  
Binding Protein ◽  
Antibody Fragment ◽  
Neutralizing Antibody ◽  
Active Immunization ◽  
Single Chain ◽  
Single Chain Antibody ◽  
Duffy Binding Protein ◽  
Erythrocyte Binding

ABSTRACT Phage display of single-chain variable fragment (scFv) antibodies is a powerful tool for selecting important, useful, and specific human antibodies. We constructed a library from three patients infected with Plasmodium vivax. Panning on recombinant PvRII enriched a population of scFvs that recognized region II of the P. vivax Duffy binding protein (DBP). Three clones of scFvs that reacted with PvRII were selected, and their biological functions were analyzed. These scFvs inhibited erythrocyte binding to DBP. Clone SFDBII92 had the greatest affinity (dissociation constant = 3.62 × 10−8 M) and the greatest inhibition activity (50% inhibitory concentration ≈ 2.9 μg/ml) to DBP. Thus, we demonstrated that human neutralizing antibody could be made from malaria patients using phage display and that these neutralizing scFvs should prove valuable for developing both passive and active immunization strategies based on DBP.

scholarly journals Mapping Epitopes of the Plasmodium vivax Duffy Binding Protein with Naturally Acquired Inhibitory Antibodies

2009 ◽  
Vol 78 (3) ◽  
pp. 1089-1095 ◽  
Author(s):  
Patchanee Chootong ◽  
Francis B. Ntumngia ◽  
Kelley M. VanBuskirk ◽  
Jia Xainli ◽  
Jennifer L. Cole-Tobian ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
Binding Protein ◽  
High Titer ◽  
Blood Stage ◽  
Duffy Binding Protein ◽  
Linear Peptide ◽  
Binding Function ◽  
Blood Stage Infection ◽  
Erythrocyte Binding ◽  
Linear Epitopes

ABSTRACT Plasmodium vivax Duffy binding protein (DBP) is a merozoite microneme ligand vital for blood-stage infection, which makes it an important candidate vaccine for antibody-mediated immunity against vivax malaria. A differential screen with a linear peptide array compared the reactivities of noninhibitory and inhibitory high-titer human immune sera to identify target epitopes associated with protective immunity. Naturally acquired anti-DBP-specific serologic responses observed in the residents of a region of Papua New Guinea where P. vivax is highly endemic exhibited significant changes in DBP-specific titers over time. The anti-DBP functional inhibition for each serum ranged from complete inhibition to no inhibition even for high-titer responders to the DBP, indicating that epitope specificity is important. Inhibitory immune human antibodies identified specific B-cell linear epitopes on the DBP (SalI) ligand domain that showed significant correlations with inhibitory responses. Affinity-purified naturally acquired antibodies on these epitopes inhibited the DBP erythrocyte binding function greatly, confirming the protective value of specific epitopes. These results represent an important advance in our understanding of part of blood-stage immunity to P. vivax and some of the specific targets for vaccine-elicited antibody protection.

scholarly journals Genetic Diversity in New Members of the Reticulocyte Binding Protein Family in Thai Plasmodium vivax Isolates

PLoS ONE ◽  
2012 ◽  
Vol 7 (3) ◽  
pp. e32105 ◽  
Author(s):  
Varakorn Kosaisavee ◽  
Usa Lek-Uthai ◽  
Rossarin Suwanarusk ◽  
Anne Charlotte Grüner ◽  
Bruce Russell ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Plasmodium Vivax ◽  
Binding Protein ◽  
Protein Family ◽  
New Members

scholarly journals Correction: Genetic Diversity in New Members of the Reticulocyte Binding Protein Family in Thai Plasmodium vivax Isolates

PLoS ONE ◽  
2012 ◽  
Vol 7 (6) ◽  
Author(s):  
Varakorn Kosaisavee ◽  
Usa Lek-Uthai ◽  
Rossarin Suwanarusk ◽  
Anne Charlotte Grüner ◽  
Bruce Russell ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Plasmodium Vivax ◽  
Binding Protein ◽  
Protein Family ◽  
New Members

scholarly journals Genetic diversity, natural selection and haplotype grouping of Plasmodium vivax Duffy-binding protein genes from eastern and western Myanmar borders

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Yubing Hu ◽  
Lin Wang ◽  
Huguette Gaelle Ngassa Mbenda ◽  
Myat Thu Soe ◽  
Chunyun Yu ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Natural Selection ◽  
Genetic Differentiation ◽  
Plasmodium Vivax ◽  
Binding Protein ◽  
Duffy Binding Protein ◽  
High Genetic Diversity ◽  
Low Level ◽  
Malaria Epidemiology ◽  
Greater Mekong Subregion

Abstract Background Merozoite proteins of the malaria parasites involved in the invasion of red blood cells are selected by host immunity and their diversity is greatly influenced by changes in malaria epidemiology. In the Greater Mekong Subregion (GMS), malaria transmission is concentrated along the international borders and there have been major changes in malaria epidemiology with Plasmodium vivax becoming the dominant species in many regions. Here, we aimed to evaluate the genetic diversity of P. vivax Duffy-binding protein gene domain II (pvdbp-II) in isolates from the eastern and western borders of Myanmar, and compared it with that from global P. vivax populations. Methods pvdbp-II sequences were obtained from 85 and 82 clinical P. vivax isolates from the eastern and western Myanmar borders, respectively. In addition, 504 pvdbp-II sequences from nine P. vivax populations of the world were retrieved from GenBank and used for comparative analysis of genetic diversity, recombination and population structure of the parasite population. Results The nucleotide diversity of the pvdbp-II sequences from the Myanmar border parasite isolates was not uniform, with the highest diversity located between nucleotides 1078 and 1332. Western Myanmar isolates had a unique R391C mutation. Evidence of positive natural selection was detected in pvdbp-II gene in P. vivax isolates from the eastern Myanmar area. P. vivax parasite populations in the GMS, including those from the eastern, western, and central Myanmar as well as Thailand showed low-level genetic differentiation (FST, 0.000–0.099). Population genetic structure analysis of the pvdbp-II sequences showed a division of the GMS populations into four genetic clusters. A total of 60 PvDBP-II haplotypes were identified in 210 sequences from the GMS populations. Among the epitopes in PvDBP-II, high genetic diversity was found in epitopes 45 (379-SIFGT(D/G)(E/K)(K/N)AQQ(R/H)(R/C)KQ-393, π = 0.029) and Ia (416-G(N/K)F(I/M)WICK(L/I)-424], Ib [482-KSYD(Q/E)WITR-490, π = 0.028) in P. vivax populations from the eastern and western borders of Myanmar. Conclusions The pvdbp-II gene is genetically diverse in the eastern and western Myanmar border P. vivax populations. Positive natural selection and recombination occurred in pvdbp-II gene. Low-level genetic differentiation was identified, suggesting extensive gene flow of the P. vivax populations in the GMS. These results can help understand the evolution of the P. vivax populations in the course of regional malaria elimination and guide the design of PvDBP-II-based vaccine.

scholarly journals Epigenetic editing by CRISPR/dCas9 in Plasmodium falciparum

2018 ◽  
Vol 116 (1) ◽  
pp. 255-260 ◽  
Author(s):  
Bo Xiao ◽  
Shigang Yin ◽  
Yang Hu ◽  
Maoxin Sun ◽  
Jieqiong Wei ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Target Genes ◽  
Genetic Manipulation ◽  
Essential Gene ◽  
Binding Protein ◽  
Transcriptional Level ◽  
Invasion Pathways ◽  
Powerful Approach ◽  
Erythrocyte Binding ◽  
Short Palindromic Repeat

Genetic manipulation remains a major obstacle for understanding the functional genomics of the deadliest malaria parasite Plasmodium falciparum. Although the CRISPR/Cas9 (clustered regularly interspaced short palindromic repeat/CRISPR-associated protein 9) system has been successfully applied to introduce permanent changes in the parasite genome, its use is still limited. Here we show that fusing different epigenetic effector domains to a Cas9 null mutant efficiently and specifically reprograms the expression of target genes in P. falciparum. By precisely writing and erasing histone acetylation at the transcription start site regions of the invasion-related genes reticulocyte binding protein homolog 4 (rh4) and erythrocyte binding protein 175 (eba-175), respectively, we achieved significant activation of rh4 and repression of eba-175, leading to the switch of the parasite invasion pathways into human erythrocytes. By using the epigenetic knockdown system, we have also characterized the effects of PfSET1, previously identified as an essential gene, on expression of mainly trophozoite- and schizont-specific genes, and therefore regulation of the growth of the mature forms of P. falciparum. This epigenetic CRISPR/dCas9 system provides a powerful approach for regulating gene expression at the transcriptional level in P. falciparum.

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