Julian Mwanguzi's research works | London School of Hygiene and Tropical Medicine and other places

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Figure 1. Proportion of different detection methods positive for malaria. Histidine-rich protein 2 (HRP2)based rapid diagnostic tests (RDTs) generated more positive samples compared to other methods. PCR methods produced 13-20% more positive results compared to microscopy.

Figure 2. Flow diagram showing the strategy for determining deletion of pfhrp2 and pfhrp3 genes. Total of 274 Plasmodium falciparum samples were amplified using 18SrDNA PCR. All the positives (131 samples) were then subjected to pfhrp2 and pfhrp3 PCR amplifications. Pfhrp2 and pfhrp3 negative samples (64 and 38 respectively) were then further subjected to PCR amplification using msp1 and msp2 primers to confirm the presence of parasites. Pfhrp2 and pfhrp3 PCR amplification were repeated if the samples were msp1/msp2 and 18SrDNA positive but pfhrp2/pfhrp3 negative (33 and 31 respectively). A qPCR analysis was then performed on those samples negative by pfhrp2 and pfhrp3 but positive by other PCR methods (25 and 31 respectively). Samples with parasitaemia less than 5 parasites per microliter were excluded (11 and 30 respectively). The upstream and downstream flanking regions of pfhrp2 and pfhrp3 for the remaining samples were then amplified using specific primers (14 and 1 respectively). To reduce the risk of false pfhrp2-negative due to low parasite density, only microscopy positive samples were called pfhrp2 and pfhrp3 deletions (8 samples for pfhrp2 only).

Figure 4. Coverage analysis of pfhrp2 and pfhrp3 genes using whole genome sequencing data from Kilifi, eastern Kenya. (A) Scatterplot of the percentage of genome with coverage (i.e., percentage of positions with at least one read mapped) versus percentage of reads that could be mapped on the 3D7 reference genome before quality checks (n = 61). Vertical and horizontal lines indicate the quality control cut-off used in the analysis while grey and white dots represent the genomes selected and not selected for the subsequent coverage analysis. (B) Scatterplot of the percentage of positions of pfhrp2 and pfhrp3 genes with no coverage after quality checks (n = 49). Red dots in A and B represent samples with possible evidence for a deletion in either gene. (C and D) Coverage profiles of the pfhrp2 and pfhrp3 genes and their respective 2 kb flanking regions to the either side for two genomes with possible evidence for a deletion in either gene, where dotted lines represent the average coverage of the whole genome in the respective samples.

Plasmodium falciparum parasites with histidine-rich protein 2 (pfhrp2) and pfhrp3 gene deletions in two endemic regions of Kenya

November 2017

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Deletions of the Plasmodium falciparum hrp2 and hrp3 genes can affect the performance of HRP2-based malaria rapid diagnostic tests (RDTs). Such deletions have been reported from South America, India and Eritrea. Whether these parasites are widespread in East Africa is unknown. A total of 274 samples from asymptomatic children in Mbita, western Kenya, and 61 genomic data from Kilifi, eastern Kenya, were available for analysis. PCR-confirmed samples were investigated for the presence of pfhrp2 and pfhrp3 genes. In samples with evidence of deletion, parasite presence was confirmed by amplifying three independent genes. We failed to amplify pfhrp2 from 25 of 131 (19.1%) PCR-confirmed samples. Of these, only 8 (10%) samples were microscopic positive and were classified as pfhrp2-deleted. Eight microscopically-confirmed pfhrp2-deleted samples with intact pfhrp3 locus were positive by HRP2-based RDT. In addition, one PCR-confirmed infection showed a deletion at the pfhrp3 locus. One genomic sample lacked pfhrp2 and one lacked pfhrp3. No sample harbored parasites lacking both genes. Parasites lacking pfhrp2 are present in Kenya, but may be detectable by HRP-based RDT at higher parasitaemia, possibly due to the presence of intact pfhrp3. These findings warrant further systematic study to establish prevalence and diagnostic significance.

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Supplementary Material

November 2017

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... Nonetheless, in the context of malaria control and elimination, even low-density infections can be infectious to mosquitoes, maintaining transmission in the population, and are thus important to identify and treat [13,38,56]. While majority of subpatent infections are due to low density parasitaemia; in situations where HRP2-based RDTs are used, deletion of the histidine-rich protein 2 and histidine-rich protein 3 genes (pfhrp2 and pfhrp3) has also been implicated as a reason for the failure of RDTs to detect P. falciparum even with higher density infections [57][58][59]. It is important to continue monitoring for the occurrence and spread of hrp2/3 gene deleted parasites. ...
Reference:
Prevalence of subpatent Plasmodium falciparum infections in regions with varying transmission intensities and implications for malaria elimination in Mainland Tanzania

Plasmodium falciparum parasites with histidine-rich protein 2 (pfhrp2) and pfhrp3 gene deletions in two endemic regions of Kenya

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November 2017

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Julian Mwanguzi’s research while affiliated with London School of Hygiene and Tropical Medicine and other places

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