Abstract
BackgroundThe Senegalese National Malaria Control Programme has recommended use of rapid diagnostic tests (RDTs) that target the histidine-rich protein 2 (HRP2), specific to Plasmodium falciparum, to diagnose malaria cases. The target antigen has been shown to be polymorphic, which may explain the variability in HRP2-based RDT results reported in field studies. The genetic diversity of the pfhrp2 gene has not been investigated in depth in many African countries. The goal of this study is to determine the extent of polymorphism in pfhrp2 among Senegal, Mali and Uganda parasite populations, and discuss the implications of these findings on the utility of RDTs that are based on HRP2 detection.MethodsSequencing data from the pfhrp2 locus were used to analyze the genetic diversity of this gene among three populations, with different transmission dynamics and malaria parasite ecologies. Nucleotide diversity (π) and non-synonymous nucleotide diversity (πNS) were studied in the pfhrp2 gene from isolates obtained in Senegal. Amino acid repeat length polymorphisms in the PfHRP2 antigen were characterized and parameters of genetic diversity, such as frequency and correlation between repeats in these populations, were assessed.ResultsThe diversity survey of the pfhrp2 gene identified 29 SNPs as well as insertion and deletion polymorphisms within a 918 bp region. The Senegal pfhrp2 exhibited a substantial level of diversity [π = 0.00559 and πNS = 0.014111 (πS = 0.0291627)], similar to several polymorphic genes, such as msp1, involved in immune responses, and the gene encoding the SURFIN polymorphic antigen, which are surface exposed parasite proteins. Extensive repeat length polymorphisms in PfHRP2, as well as similar patterns in the number, organization and the type of predicted amino acid repeats were observed among the three populations, characterized by an occurrence of Type 2, Type 4 and Type 7 repeats.ConclusionsThese results warrant deeper monitoring of the RDT target antigen diversity and emphasize that development of other essential genes as a target for diagnostic tools is critical.
Highlights
The Senegalese National Malaria Control Programme has recommended use of rapid diagnostic tests (RDTs) that target the histidine-rich protein 2 (HRP2), specific to Plasmodium falciparum, to diagnose malaria cases
In Senegal, HRP2based RDTs are most commonly used in health facilities because of their previously demonstrated sensitivity and specificity and because P. falciparum represents the major Plasmodium species in Senegal [12], with P. malariae and P. ovale comprising less than 2% of malaria cases, and no P. vivax (0%) observed in 2013 [4]
Previous reports from Mali have indicated the loss of the HRP2 locus from some parasites, and this study investigates whether changes in this locus among Senegalese parasites may compromise the performance of the RDTs so widely used for malaria diagnosis
Summary
The Senegalese National Malaria Control Programme has recommended use of rapid diagnostic tests (RDTs) that target the histidine-rich protein 2 (HRP2), specific to Plasmodium falciparum, to diagnose malaria cases. Some are based on detection of the P. falciparum specific histidine-rich protein-2 (PfHRP2), or P. falciparum specific lactate dehydrogenase (PfLDH), while others recognize antigens common to P. falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae (pan-species pLDH and aldolase) [7]. In Senegal, HRP2based RDTs are most commonly used in health facilities because of their previously demonstrated sensitivity and specificity and because P. falciparum represents the major Plasmodium species (more than 98%) in Senegal [12], with P. malariae and P. ovale comprising less than 2% of malaria cases, and no P. vivax (0%) observed in 2013 [4]
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