Sequence variation in Plasmodium falciparum Histidine Rich Proteins 2 and 3 in Indian isolates: Implications for Malaria Rapid Diagnostic Test Performance

Bharti, Praveen K.; Chandel, Himanshu Singh; Krishna, Sri; Nema, Shrikant; Ahmad, Amreen; Udhayakumar, Venkatachalam; Singh, Neeru

doi:10.1038/s41598-017-01506-9

Cited by 31 publications

(39 citation statements)

References 18 publications

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“…Thus, the genetic variation in pfhrp2 does not appear to affect RDT detection sensitivity at ³ 200 parasites/μL. 9 Consistent with Baker et al's subsequent conclusion, similar results have been reported by Kumar Bharti et al 11 using P. falciparum-positive blood samples collected from 15 sites in eight malaria-endemic states in India and by Willie et al 12 using samples collected from three health centers in the Ampasimpotsy area in Madagascar.…”

Section: Introductionsupporting

confidence: 77%

“…9,10 Detection sensitivity for different RDTs tested in different populations in PNG was as low as 45.6% 7 to as high as 96%. 6 Although the correlation between RDT performance and pfhrp2 variation remains unclear, [9][10][11][12] the studies that have tested RDTs in PNG did not analyze pfhrp2 variation. [3][4][5][6][7] All 18 sequences in the present study were generated from 12 samples that were P. falciparum positive by LDR-FMA.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, it is difficult to predict whether all these samples would be detected or not by an RDT. Given the field sample-based observations made by Kumar Bharti et al 11 and Willie et al, 12 verification of these RDT detection predictions made on the basis of the repeat numbers is required, particularly for the samples that had very low (< 50 parasites/μL) or submicroscopic parasitemia levels.…”

Section: Discussionmentioning

confidence: 99%

“…The pfhrp2 gene sequences were translated into protein sequences and 24 amino acid repeat types (1-24) were classified as described by Baker et al 9,10 Of these 24 amino acid repeat types (called Baker repeats), 20 (repeats [1][2][3][4][5][6][7][8][9][10][11][12][13][14][19][20][21][22][23][24] are present in pfhrp2, whereas four (repeats 15-18) are present in the pfhrp2 paralog gene pfhrp3. 9 Because RDT-based diagnosis was not performed on these samples, 14 both scenarios of the predictive model, based on the number of type 2 × type 7 repeats, were used to predict the sensitivity of an RDT detecting PfHRP2: (a) an isolate would be detectable at £ 250 parasites/μL if the number of repeat types is > 43 10 and (b) an isolate would be detectable at ³ 200 parasites/μL regardless of the number of repeat types.…”

Section: Introductionmentioning

confidence: 99%

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Plasmodium falciparum Histidine-Rich Protein 2 Gene Variation in a Malaria-Endemic Area of Papua New Guinea

Willie

Zimmerman

Mehlotra

2018

The American Journal of Tropical Medicine and Hygiene

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Histidine-rich protein 2 of (PfHRP2) forms the basis of many current malaria rapid diagnostic tests (RDTs). It is concerning that there are parasites that lack part or all of the gene, and thus do not express the PfHRP2 protein; such parasites are not identifiable by PfHRP2-detecting RDTs. Very limited information is available regarding genetic variation in Papua New Guinea (PNG). In the present study, this gene variation was evaluated using 169 samples previously collected from the Wosera area in East Sepik Province of PNG. Molecular diagnosis of these samples showed that 81% were infected, and was present in 91% of those infected samples. One hundred and twenty samples were amplified for exon-2, from which 12 randomly selected amplicons were sequenced, yielding 18 sequences, all of which were unique. Baker repeat type 2 × type 7 numbers ranged from 0 to 108. Epitope mapping analysis revealed that three major epitopes, DAHHAHHA, AHHAADAHHA, and AHHAADAHH, were present in high prevalence and frequencies. These major epitopes have been shown to be recognized by the monoclonal antibodies 3A4 and PTL-3 (DAHHAHHA), C1-13 (AHHAADAHHA), and S2-5 and C2-3 (AHHAADAHH). This study provides further information on the high genetic variation of and its unclear relationship with prediction of RDT detection sensitivity, and identifies major epitopes in this gene from PNG. These results could be relevant and useful to understand the genetic diversity of this gene and the performance of current and future RDTs in this malarious region of the world.

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Section: Introductionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Plasmodium falciparum Histidine-Rich Protein 2 Gene Variation in a Malaria-Endemic Area of Papua New Guinea

Willie

Zimmerman

Mehlotra

2018

The American Journal of Tropical Medicine and Hygiene

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“…If the prevalence of deletion is calculated taking account the number of Pf detected by SnM-PCR (763) the frequencies for each case were: deletion in both genes, 10…”

Section: Resultsmentioning

confidence: 99%

First evidence of the deletion in the Pfhrp2 and Pfhrp3 genes in P. falciparum from Equatorial Guinea

Berzosa

González

Taravillo

et al. 2019

Preprint

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Background: WHO recommends RDTs as a good alternative malaria-diagnosis method in remote parts of sub-Saharan Africa. The majority of commercial RDTs currently available detect the P. falciparum protein histidine-rich protein 2 (PfHRP2). There have also been recent reports of Pfhrp2 deletions being found in parasites collected from several African countries. WHO has concluded that the lacking the Pfhrp2 gene must be monitored in Africa. The purpose of the study was to analyze why the samples that were positive by PCR were negative by RDTs; and, therefore, to determine whether there have been deletions in the Pfhrp2 and/or Pfhrp3 genes. Methods: Malaria NM-PCR was carried out to all the samples collected in the field. A group of 128 samples was positive by PCR but negatives by RDT, these samples were classified as RDT false-negatives. It was carried out a PCR for exon2 of Pfhrp2 and Pfhrp3 genes to detect the presence or absence of these two genes. Frequencies with 95% confidence intervals (CIs) were used for categorical variables. Associations were assessed by the chi-square test or Fisher´s exact test. The level of significance was set at p ≤ 0.05. Statistical analyses were performed using the software package SPSSv.15.0. Sensitivity and specificity calculations were performed using Epidat 3.1 software. Results: After the PCR, 81 samples were identified (4.7%, 95%CI: 3.8-5.8) which had deletion in both genes, Pfhrp2 and Pfhrp3. Overall, however, 11 samples (0.6%, 95%CI: 0.36-1.14) had deletion only in Pfhrp2 but not in Pfhrp3, and 15 (0.9%, 95%CI: 0.6-1.5) presented with deletion only in Pfhrp3 but not in Pfhrp2. Considering the Pfhrp2 gene separately, within the total of 1,724 samples, 92 (5.3%, 95%CI: 4.37-6.5) had evidence of deletion. Conclusion: The present study provides the first evidence of deletion in the Pfhrp2 and Pfhrp3 genes in P. falciparum isolates from Equatorial Guinea. However, larger studies across different regions within the country and across different seasonal profiles are needed to determine the full extent of Pfhrp2- and Pfhrp3-deletion. it would be strongly recommendable to implement an active surveillance program in order to detect any increases in Pfhrp2- and Pfhrp3-deletion frequencies.

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Genetic diversity and deletion of Plasmodium falciparum histidine-rich protein 2 and 3: a threat to diagnosis of P. falciparum malaria

Gendrot

Fawaz²,

Dormoi

et al. 2019

Clinical Microbiology and Infection

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Background: PfHRP2-based rapid diagnostic tests (RDTs), based on the recognition of the Plasmodium falciparum histidine-rich protein 2, are currently the most used tests in malaria detection. Most of the antibodies used in RDTs also detect PfHRP3. However, false-negative results were reported. Significant variation in the pfhrp2 gene could lead to the expression of a modified protein that would no longer be recognized by the antibodies used in PfHRP2-based RDTs. Additionally, parasites lacking the PfHRP2 do not express the protein and are, therefore, not identifiable. Aims: This review aims to assess the pfhrp2 and pfhrp3 genetic variation or the prevalence of gene deletion in areas where malaria is endemic and describe its implications on RDT use. Sources: Publications of interest were identified using PubMed, Google Scholar and Google. Content: More than 18 types of amino acid repeats were identified from the PfHRP2 sequences. Sequencing analysis revealed high-level genetic variation in the pfhrp2 and pfhrp3 genes (>90% of variation in Madagascar, Nigeria or Senegal) both within and between countries. However, genetic variation of PfHRP2 and PfHRP3 does not seem to be a major cause of false-negative results. The countries that showed the highest proportions of pfhrp2-negative parasites were Peru (20%e100%) and Guyana (41%) in South America, Ghana (36%) and Rwanda (23%) in Africa. High prevalence of pfhrp2 deletion causes a high rate of false-negatives results. Implications: Presence of parasites lacking the pfhrp2 gene may pose a major threat to malaria control programmes because P. falciparum-infected individuals are not diagnosed and properly treated.

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Sequence variation in Plasmodium falciparum Histidine Rich Proteins 2 and 3 in Indian isolates: Implications for Malaria Rapid Diagnostic Test Performance

Cited by 31 publications

References 18 publications

Plasmodium falciparum Histidine-Rich Protein 2 Gene Variation in a Malaria-Endemic Area of Papua New Guinea

Plasmodium falciparum Histidine-Rich Protein 2 Gene Variation in a Malaria-Endemic Area of Papua New Guinea

First evidence of the deletion in the Pfhrp2 and Pfhrp3 genes in P. falciparum from Equatorial Guinea

Genetic diversity and deletion of Plasmodium falciparum histidine-rich protein 2 and 3: a threat to diagnosis of P. falciparum malaria

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