Genetic diversity of Plasmodium falciparum histidine-rich protein 2 in the China–Myanmar border area

Li, Peipei; Hua, Xinyang; Zhao, Zhenjun; Yang, Zhaoqing; Cao, Yaming; Li, Wenli; Yan, Guiyun; Sattabongkot, Jetsumon; Cui, Liwang; Fan, Qi

doi:10.1016/j.actatropica.2015.08.003

Cited by 59 publications

(58 citation statements)

References 29 publications

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“…Further, high prevalence of hrp2 deletion were observed compared to hrp3 deletion in all four regions. Similar predominant hrp2 deletion strains have been reported in previous studies from India [ 30 ] and Suriname [ 21 ], which are in contrast to other studies [ 17 – 19 , 47 , 38 – 40 , 48 , 49 ], where the frequency of hrp3 deletion was higher. Interestingly, high proportions of hrp2 deletion parasites were observed during summer, whereas the proportions of hrp2 deletion and hrp3 deletion parasites were nearly the same in peak season of malaria transmission (Table 1 ).…”

Section: Discussionsupporting

confidence: 89%

High proportions of pfhrp2 gene deletion and performance of HRP2-based rapid diagnostic test in Plasmodium falciparum field isolates of Odisha

Pati

Dhangadamajhi

Bal

et al. 2018

Malar J

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BackgroundWith the documentation of cases of falciparum malaria negative by rapid diagnostic tests (RDT), though at low frequency from natural isolates in a small pocket of Odisha, it became absolutely necessary to investigate the status of HRP-2 based RDT throughout the state and in different seasons of the year.MethodsSuspected individuals were screened for malaria infection by microscopy and RDT in 25/30 districts of Odisha, India. Discrepancies in results were confirmed by PCR. False negative RDT samples for Plasmodium falciparum mono-infection were evaluated for detection of HRP2 antigen in ELISA and genotyped for pfhrp2, pfhrp3 and their flanking genes. Multiplicity of infection was ascertained based on msp1 and msp2 genotyping and parasitaemia level was determined by microscopy.ResultsOf the total 1058 patients suspected for malaria, 384 were microscopically confirmed for P. falciparum mono-infection and RDT failure was observed in 58 samples at varying proportion in different regions of the state. The failure in detection was due to undetectable level of HRP-2. Although most of these samples were screened during rainy season (45/345), significantly high proportion (9/17) of RDT negative samples were obtained during the summer compared to rainy season (P = 0.0002; OR = 7.5). PCR genotyping of pfhrp2 and pfhrp3 in RDT negative samples showed 38/58 (65.5) samples to be pfhrp2 negative and 24/58 (41.4) to be pfhrp3 negative including dual negative in 17/58 (29.3). Most of the RDT negative samples (39/58) were with single genotype infection and high proportions of pfhrp2 deletion (7/9) was observed in summer. No difference in parasitaemia level was observed between RDT positive and RDT negative patients.ConclusionHigh prevalence of parasites with pfhrp2 deletion including dual deletions (pfhrp2 and pfhrp3) is a serious cause of concern, as these patients could not be given a correct diagnosis and treatment. Therefore, HRP2-based RDT for diagnosing P. falciparum infection in Odisha is non-reliable and must be performed in addition to or replaced by other appropriate diagnostic tools for clinical management of the disease.Electronic supplementary materialThe online version of this article (10.1186/s12936-018-2502-3) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 89%

High proportions of pfhrp2 gene deletion and performance of HRP2-based rapid diagnostic test in Plasmodium falciparum field isolates of Odisha

Pati

Dhangadamajhi

Bal

et al. 2018

Malar J

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“…South America was the first region to report the occurrence of false negative RDT results due to this gene deletion (Gamboa et al, 2010;Akinyi et al, 2013;Abdallah et al, 2015;Akinyi Okoth et al, 2015;Murillo Solano et al, 2015;Rachid Viana et al, 2017). Similar evidence was followed by more recent studies from Africa (Dolo et al, 2012;Wurtz et al, 2013;Parr et al, 2016;Beshir et al, 2017) and Asia (Kumar et al, 2013;Li et al, 2015;Bharti et al, 2016). Driven by the high impact of pfhrp2-detecting RDT use on malaria control, mathematical modelling exercises have identified low transmission regions of sub-Saharan Africa as the priority for pfhrp2-deletion investigations (Watson et al, 2017).…”

Section: Introductionmentioning

confidence: 82%

“…Of these, six studies were excluded from the analysis, because they did not evaluate pfhrp2 and pfhrp3 deletions in the field (Ramutton et al, 2012;Mendoza et al, 2013;Das et al, 2018;Parr et al, 2018) or referred to case studies (Houzé et al, 2011;Johora et al, 2017). Other six studies determined the combined genotypes of pfhrp2 and pfhrp3 status only on a subset of samples with negative RDT result (Kumar et al, 2013;Wurtz et al, 2013;Li et al, 2015;Bharti et al, 2016;Parr et al, 2016;Gupta et al, 2017). These studies were discarded from the analysis, because the respective data were intrinsically incomplete and biased by study design.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Global analysis of Plasmodium falciparum histidine-rich protein-2 (pfhrp2) and pfhrp3 gene deletions using whole-genome sequencing data and meta-analysis

Sepúlveda

Phelan

Benavente

et al. 2018

Infection, Genetics and Evolution

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Many rapid diagnostic tests (RDT) used on suspected malaria cases are based on the detection of the protein encoded by the Plasmodium falciparum histidine-rich protein-2 (pfhrp2) gene, which shares a high sequence homology with pfhrp3 in the 3D7 reference genome. Parasite isolates showing pfhrp2 and pfhrp3 gene deletions have been emerging over the years, but a comprehensive genetic analysis of these variants is still lacking. With this purpose, genomic data from experimental P. falciparum genetic crosses between different laboratory lines (3D7, HB3, DD2, 7G8 and GB4) were first analysed (n = 98). The frequency of pfhrp2 deletions was consistent with a Mendelian prediction in HB3 × DD2 (56.7%; 95%CI = (39.5%-72.9%)). Moreover, the pfhrp2 and pfhrp3 deletions segregated independently of each other in the same genetic cross. Analysis of 3D7 × HB3 and 7G8 × GB4 estimated the probability of spontaneously generating a pfhrp2 deletion during sexual recombination to be up to 6.2%. Next, whole genome sequence data from 1970 P. falciparum isolates collected globally were analysed. Nine samples displayed depth of coverage consistent with pfhrp2 deletions (0.5%), but the corresponding split-read analysis could not confirm deletions in seven of these samples. Twenty-eight isolates had evidence of pfhrp3 deletions (1.4%), which are widespread in Southeast Asia. Finally, a meta-analysis of published data revealed a positive mean association between the frequencies of pfhrp2 and pfhrp3 deletions in Africa and South America. This result suggested a shared selective pressure acting on these genetic variants. In conclusion, evidence of genetic selection on both pfhrp2 and pfhrp3 deletions was presented, but experimental crosses do not provide evidence of a fitness cost of these variants. Further work is urgently needed to accurately determine the prevalence and the degree of association between these genetic variants, and the respective impact on diagnostic accuracy of many in-use RDT.

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“…Phylogenetic analysis of the Ghana PfHRP2 revealed striking similarities with isolates from Kenya. In a study along the Chinese-Myanmar border, novel PfHRP2 repeat types arising from replacement of a single amino acid of eight amino acid repeats types were identified [33]. Nderu et al [18] also found 39 novel PfHRP2 repeat types.…”

Section: Discussionmentioning

confidence: 99%

Plasmodium falciparum histidine-rich protein 2 (PfHRP2) diversity in Ghana

Addai‐Mensah

Dinko

Noagbe

et al. 2020

Preprint

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Background: In the absence of microscopy, Plasmodium falciparum histidine-rich proteins 2 (PfHRP2)-based rapid diagnostic tests (RDTs) are recommended for the diagnosis of falciparum malaria, particularly in endemic regions. However, genetic variability of the PfHRP2 gene threatens the usefulness of the test. This study aimed to investigate the diversity of PfHRP2 in malaria cases among children in Ghana. Methods:A cross-sectional study was conducted at the Adidome Government Hospital in the Volta Region of Ghana. A total of 50 children with mean age of 6.6±3.5 years and diagnosed of falciparum malaria were included. Blood samples were collected for complete blood count, malaria parasite identification and counting. DNA samples were amplified and sequenced. Nucleotide sequences were translated in silico to corresponding amino acids and the deduced amino acids sequences were analyzed for diversity. Results:The number of repeats and number of each repeat within PfHRP2 varied between isolates.Twelve rare PfHRP2 repeat types, two of which are previously unreported, were identified in this study. Our HRP2 sequence shared high similarity with isolates from Kenya. Using Baker's regression model, Group B was the highest occurring type (58.0%). Screening of all sequences for epitopes recognized by PfHRP2-specific monoclonal antibodies (mAbs), we found the predominant motif to be AHHAADAHH, which is recognized by the C1-13 mAbs. Conclusion:This study reports diversity of P. falciparum histidine-rich proteins 2 in samples from Ghanaian children with symptomatic malaria. We highlight the existence of extra amino acid repeat types which adds to the PfHRP2 antigenic variability. The findings of this study will contribute to the understanding of the performance of PfHRP2-based RDTs in the Ghanaian setting.accounting for not less than 20% of child deaths, 40% of child hospital admissions, and more than 50% of outpatient attendances [4][5][6][7].Although, microscopic examination of stained blood smears remains the gold standard for malaria diagnosis, its benefit is limited by the absence of adequate skilled personnel, and infrastructural and logistic resources, particularly in resource-poor areas [8]. To overcome this problem, the World Health Organization (WHO) included rapid diagnostic tests (RDTs), a relatively less expensive and easily accessible test, as one of the alternative testing systems for malaria diagnosis prior to the prescription of antimalarial drugs.Since its development in the 1990s, and with more than 200 currently available brands, there has been consistent reports of observable increase in malaria RDT sales worldwide [9,10]. Most of the malaria RDTs exploit the presence of P. falciparum Histidine-Rich Protein-2 (PfHRP2) for the detection of Plasmodium falciparum [11]. The presence of repetitive epitopes, that enable their detection by multiple antibodies, and their abundance in blood during the blood-stage of malaria infections has made the PfHRP2 protein a common antigenic target for RDTs [12,13].In 2010, Gh...

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Genetic diversity of Plasmodium falciparum histidine-rich protein 2 in the China–Myanmar border area

Cited by 59 publications

References 29 publications

High proportions of pfhrp2 gene deletion and performance of HRP2-based rapid diagnostic test in Plasmodium falciparum field isolates of Odisha

High proportions of pfhrp2 gene deletion and performance of HRP2-based rapid diagnostic test in Plasmodium falciparum field isolates of Odisha

Global analysis of Plasmodium falciparum histidine-rich protein-2 (pfhrp2) and pfhrp3 gene deletions using whole-genome sequencing data and meta-analysis

Plasmodium falciparum histidine-rich protein 2 (PfHRP2) diversity in Ghana

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