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National genomic profiling of Plasmodium falciparum antimalarial resistance in Zambian children participating in the 2018 Malaria Indicator Survey.

ABSTRACT: The emergence of antimalarial drug resistance is a major threat to malaria control and elimination. Using whole genome sequencing of 282 P. falciparum samples collected during the 2018 Zambia National Malaria Indicator Survey, we determined the prevalence and spatial distribution of known and candidate antimalarial drug resistance mutations. High levels of genotypic resistance were found across Zambia to pyrimethamine, with over 94% (n=266) of samples having the Pfdhfr triple mutant (N51I, C59R, and S108N), and sulfadoxine, with over 84% (n=238) having the Pfdhps double mutant (A437G and K540E). In northern Zambia, 5.3% (n=15) of samples also harbored the Pfdhps A581G mutation. Although 29 mutations were identified in Pfkelch13, these mutations were present at low frequency (<2.5%), and only three were WHO-validated artemisinin partial resistance mutations: P441L (n=1, 0.35%), V568M (n=2, 0.7%) and R622T (n=1, 0.35%). Notably, 91 (32%) of samples carried the E431K mutation in the Pfatpase6 gene, which is associated with artemisinin resistance. No specimens carried any known mutations associated with chloroquine resistance in the Pfcrt gene (codons 72-76). P. falciparum strains circulating in Zambia were highly resistant to sulfadoxine and pyrimethamine but remained susceptible to chloroquine and artemisinin. Despite this encouraging finding, early genetic signs of developing artemisinin resistance highlight the urgent need for continued vigilance and expanded routine genomic surveillance to monitor these changes.

SUBMITTER: Fola AA

PROVIDER: S-EPMC11326323 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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National genomic profiling of Plasmodium falciparum antimalarial resistance in Zambian children participating in the 2018 Malaria Indicator Survey.

Fola Abebe A AA Ciubotariu Ilinca I II Dorman Jack J Mwenda Mulenga C MC Mambwe Brenda B Mulube Conceptor C Kasaro Rachael R Hawela Moonga B MB Hamainza Busiku B Miller John M JM Bailey Jeffrey A JA Moss William J WJ Bridges Daniel J DJ Carpi Giovanna G

medRxiv : the preprint server for health sciences 20240806

The emergence of antimalarial drug resistance is a major threat to malaria control and elimination. Using whole genome sequencing of 282 P. falciparum samples collected during the 2018 Zambia National Malaria Indicator Survey, we determined the prevalence and spatial distribution of known and candidate antimalarial drug resistance mutations. High levels of genotypic resistance were found across Zambia to pyrimethamine, with over 94% (n=266) of samples having the Pfdhfr triple mutan ...[more]

PMID: 39148823

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Project description:BackgroundThe proliferation of Plasmodium parasites resistant to antimalarial drugs poses a serious threat to human life and remains an obstacle to managing and eradicating Plasmodium falciparum. The surveillance of molecular markers has become necessary to monitor the spread of resistant haplotypes and discover emerging mutations.ObjectiveThis molecular epidemiological study aimed to evaluate the prevalence of known mutations in the drug resistance genes Pfcrt, Pfmdr1, Pfdhfr and Pfdhps in the Central Region of Ghana.DesignA multi-centre cross-sectional study.MethodsThis prospective study utilised dried blood spots from individuals with P. falciparum-infection from five districts in the Central Region of Ghana. Selective Whole Genome Amplification (sWGA) and Single Nucleotide Polymorphisms (SNPs) in P. falciparum chloroquine transporter genes (Pfcrt), P. falciparum multidrug resistance 1 (Pfmdr1), P. falciparum dihydropteroate synthase (Pfdhps) and P. falciparum dihydrofolate reductase (Pfdhfr) were analysed.ResultsWhole genome sequencing was carried out on 522 samples. Of these, 409 (78%) samples were successfully sequenced. Six (6) of the sequenced samples were of co-infection of other parasite species with P. falciparum and excluded from the analysis. Analysis of the Pfcrt gene revealed 0.5% were CVIET (C72, V73, M74I, N75E, K76T) while the Pfcrt CVMNK (C72, V73, M74, N75, K76) wild-type haplotypes were 97% with (2.5%) (CV[M/I][N/E][K/T]) being mixed haplotypes. In the Pfmdr1 gene, monoclonal haplotypes; NFD (N86, Y184F, D1246) and YFN (N86Y, Y184F, D1246N) occurred at 44% and 9.8%, respectively, whereas mixed- haplotypes (N[Y/F]D and [N/Y][Y/F]D) were 23.5% and 0.3%, respectively. Combined Pfdhfr/Pfdhps genes yielded about 88% Pfdhfr IRNI (N51I, C59R, S108N, I164) + Pfdhps A437G haplotypes (conferring partial resistance to Sulphadoxine-Pyrimethamine (SP)) while 9% of the parasites had Pfhdfr IRNI + Pfdhps A437G + K540E haplotypes (conferring full resistance to SP). The wild-type haplotype, Pfdhfr (N51, C59, S108, I164) and Pfdhps (S436, A437, K540, A581, A613) was not observed.ConclusionThe findings show a low prevalence of CVIET and relatively higher rates for Pfmdr1 NFD and parasites with Pfdhfr IRNI (N51I, C59R, S108N, I164) + Pfdhps A437G haplotypes. These observations advocate for enhanced surveillance which is inimical to malaria management in an endemic area.

Project description:IntroductionMalaria molecular surveillance has the potential to generate information on biological threats that compromise the effectiveness of antimalarial interventions. This study aims to streamline surveillance activities to inform the new strategic plan of the Mozambican National Malaria Control Programme (2023-2030) for malaria control and elimination.Methods and analysesThis prospective genomic surveillance study aims to generate Plasmodium falciparum genetic data to monitor diagnostic failures due to pfhrp2/3 deletions and molecular markers of antimalarial drug resistance, to characterise transmission sources and to inform the implementation of new antimalarial approaches to be introduced in Mozambique (chemoprevention and child malaria vaccination). The study, to be conducted between 2024 and 2026, will use three sampling schemes: a multicluster probabilistic health facility survey in the 10 provinces of the country to detect pfhrp2/3 deletions and markers of antimalarial drug resistance; dense sampling of all clinical cases in representative districts in the south targeted for elimination to characterise malaria importation and identify sources of transmission; and testing of pregnant women for malaria at their first antenatal care visit to assess malaria burden and molecular trends. Using a multiplex amplicon-based sequencing approach, the study will target microhaplotypes informative of genomic diversity and relatedness, as well as key drug resistance-associated genes, pfhrp2/3 deletion and malaria vaccine targets. Key genomic information will be visualised in a dashboard integrated into the District Health Information System V.2-based Malaria Information Storage System for programmatic use.Ethics and disseminationThe protocol was reviewed and approved by the national ethics committee of Mozambique (Comité Nacional de Bioética para Saúde, Ref: 680/CNBS/23). Project results will be presented to all stakeholders using study-specific brochures and published in open-access journals.Trial registration numberNCT06529237.

Project description:Host iron deficiency is protective against severe malaria as the human malaria parasite Plasmodium falciparum depends on bioavailable iron from its host to proliferate. The essential pathways of iron acquisition, storage, export, and detoxification in the parasite differ from those in humans, as orthologs of the mammalian transferrin receptor, ferritin, or ferroportin, and a functional heme oxygenase are absent in P. falciparum. Thus, the proteins involved in these processes may be excellent targets for therapeutic development, yet remain largely unknown. Here, we show that parasites cultured in erythrocytes from an iron-deficient donor displayed significantly reduced growth rates compared to those grown in red blood cells from healthy controls. Sequencing of parasite RNA revealed diminished expression of genes involved in overall metabolism, hemoglobin digestion, and metabolite transport under low-iron versus control conditions. Supplementation with hepcidin, a specific ferroportin inhibitor, resulted in increased labile iron levels in erythrocytes, enhanced parasite replication, and transcriptional upregulation of genes responsible for merozoite motility and host cell invasion. Through endogenous GFP tagging of differentially expressed putative transporter genes followed by confocal live-cell imaging, proliferation assays with knockout and knockdown lines, and protein structure predictions, we identified six proteins that are likely required for ferrous iron transport in P. falciparum. Of these, we localized PfVIT and PfZIPCO to cytoplasmic vesicles, PfMRS3 to the mitochondrion, and the novel putative iron transporter PfE140 to the plasma membrane for the first time in P. falciparum. PfNRAMP/PfDMT1 and PfCRT were previously reported to efflux Fe2+ from the digestive vacuole. Our data support a new model for parasite iron homeostasis, in which PfE140 is involved in iron uptake across the plasma membrane, PfMRS3 ensures non-redundant Fe2+ supply to the mitochondrion as the main site of iron utilization, PfVIT transports excess iron into cytoplasmic vesicles, and PfZIPCO exports Fe2+ from these organelles in case of iron scarcity. These results provide new insights into the parasite's response to differential iron availability in its environment and into the mechanisms of iron transport in P. falciparum as promising candidate targets for future antimalarial drugs.

Project description:BackgroundIn malaria endemic regions, Plasmodium falciparum infection is characterized by variable genetic diversity at different settings. The parasite's various forms are found at varied frequency in different geographic areas. Understanding malaria parasite diversity and transmission is vital to evaluate control interventions. The aim of this study was under taken to determine the status of P. falciparum genetic diversity and MOI in different regions of Ethiopia.MethodsRelevant publications were identified from electronic databases such as; PubMed, EMBASE, Google scholar and Google. Besides, an online search was done using the above databases for all articles published in English on genetic diversity of P. falciparum in Ethiopia. STATA software was used for data analysis. The pooled estimates were calculated using random effect model. The summary estimates were presented using forest plots and tables.ResultsA total of 11 studies were included in the systematic review. However, only 8, 10 and 2 studies were included for Pfmsp-1, Pfmsp-2 and glurp gene meta-analysis, respectively. However, the meta-analysis result showed that the pooled prevalence of Pfmsp-1, msp-2 and glurp gene were 84% for both msp-1/2% and 51%, respectively. The pooled prevalence of msp-1 gene was higher in Amhara followed by Oromia region and lower in SNNPR while, for msp-2 gene the pooled prevalence was higher in Benshangul gumez region. Among the allelic family of msp-1 and msp-2 genes, MAD20 (34%) and FC27 (44%) were the most predominant respectively.ConclusionBased on the review, there is evidence of the presence of high genetic diversity of P. falciparum parasites in Ethiopia, suggesting that malaria transmission remain high and that strengthened control efforts are needed. The approaches and methods used for investigation of diversified parasites have similarity between studies and should use advanced molecular techniques, like microsatellite, to assess the genetic diversity of P. falciparum for better results.

Dataset Information

National genomic profiling of Plasmodium falciparum antimalarial resistance in Zambian children participating in the 2018 Malaria Indicator Survey.

Publications

National genomic profiling of <i>Plasmodium falciparum</i> antimalarial resistance in Zambian children participating in the 2018 Malaria Indicator Survey.

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