Genomic Approaches to Drug Resistance in Malaria

Rocamora, Frances; Winzeler, Elizabeth A.

doi:10.1146/annurev-micro-012220-064343

Cited by 15 publications

(10 citation statements)

References 154 publications

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“…Furthermore, while drug resistance to artemisinin compounds has been shown to involve pfkelch13 mutations ( Ariey et al, 2014b ), additional ( Miotto et al, 2020 ) or alternative ( Demas et al, 2018 ) genetic variants may be important for this resistance such that simply tracking SNPs does not fully reflect the emergence and spread of artemisinin resistance. Finally, while monitoring genetic variants may provide information about when to assess drug efficacy ( WHO, 2020a ), these variants have limited utility for understanding the clinical response to antimalarial drugs or for detecting novel mechanisms of drug resistance ( Cowell and Winzeler, 2019 ; Rocamora and Winzeler, 2020 ; Ross and Fidock, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Genetic surveillance for monitoring the impact of drug use on Plasmodium falciparum populations

Ndiaye

Hartl

McGregor

et al. 2021

International Journal for Parasitology: Drugs and Drug Resistan

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The use of antimalarial drugs is an effective strategy in the fight against malaria. However, selection of drug resistant parasites is a constant threat to the continued use of this approach. Antimalarial drugs are used not only to treat infections but also as part of population-level strategies to reduce malaria transmission toward elimination. While there is strong evidence that the ongoing use of antimalarial drugs increases the risk of the emergence and spread of drug-resistant parasites, it is less clear how population-level use of drug-based interventions like seasonal malaria chemoprevention (SMC) or mass drug administration (MDA) may contribute to drug resistance or loss of drug efficacy. Critical to sustained use of drug-based strategies for reducing the burden of malaria is the surveillance of population-level signals related to transmission reduction and resistance selection. Here we focus on Plasmodium falciparum and discuss the genetic signatures of a parasite population that are correlated with changes in transmission and related to drug pressure and resistance as a result of drug use. We review the evidence for MDA and SMC contributing to malaria burden reduction and drug resistance selection and examine the use and impact of these interventions in Senegal. Throughout we consider best strategies for ongoing surveillance of both population and resistance signals in the context of different parasite population parameters. Finally, we propose a roadmap for ongoing surveillance during population-level drug-based interventions to reduce the global malaria burden.

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Section: Introductionmentioning

confidence: 99%

Genetic surveillance for monitoring the impact of drug use on Plasmodium falciparum populations

Ndiaye

Hartl

McGregor

et al. 2021

International Journal for Parasitology: Drugs and Drug Resistan

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“…For whole genome sequences to identify the causative mutation (42), DNA was isolated from 10 8 asexual parasites; QiAamp DNA Mini Blood kit, Qiagen), quantified (Qubit HS ds DNA assay (Qubit Flex Fluorometer, ThermoFisher)), and quality assessed by Genomic Screentape analysis (TapeStation 2200, Agilent). Barcoded libraries for DNA-Seq were synthesized from 100 ng DNA (Celero EZ-Seq kit with NuQuant, Tecan Genomics), quality assessed by High Sensitivity DNA Lab Chips (BioAnalyzer 2100, Agilent), quantified by Qubit HS dsDNA assay, and sequenced on Illumina’s MiSeq platform, (2 × 300bp v3 with 5% PhiX; JHMI Synthesis and Sequencing Facility).…”

Section: Methodsmentioning

confidence: 99%

“…For whole genome sequences to identify the causative mutation (42), DNA was isolated from Using Partek Flow with sequence defaults, analyses included pre-alignment QA/QC, adaptor/read trimming, reference genome alignment to P. falciparum NF54 (PlasmoDB) using Bowtie 2, post-alignment QA/QC, FreeBayes variant calling, variant filtering (VarQual ≥ 30), and variant annotation based on precedence rules. Sequence files for WT parent and Y268S mutant were deposited (NCBI Sequence Read Archive, BioProject ID: PRJNA913198).…”

Section: P Falciparum Cultivation and Mutant Selectionmentioning

confidence: 99%

Transmissibility of clinically relevant atovaquone-resistantPlasmodium falciparumby anopheline mosquitoes

Balta

Stiffler

Sayeed

et al. 2023

Preprint

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Rising numbers of malaria cases and deaths underscore the need for new interventions. Long-acting injectable medications, such as those now in use for HIV prophylaxis, offer the prospect of a malaria chemical vaccine, combining the efficacy of a drug (like atovaquone) with the durability of a biological vaccine. Of concern, however, is the possible selection and transmission of drug-resistant parasites. We addressed this question by generating clinically relevant, highly atovaquone-resistant, Plasmodium falciparum mutants competent to infect mosquitoes. Isogenic paired strains, that differ only by a single Y268S mutation in cytochrome b, were evaluated in parallel in southeast Asian (Anopheles stephensi) or African (Anopheles gambiae) mosquitoes, and thence in humanized mice. Fitness costs of the mutation were evident along the lifecycle, in asexual parasite growth in vitro and in a progressive loss of parasites in the mosquito. In numerous independent experiments, microscopic exam of salivary glands from hundreds of mosquitoes failed to detect even one Y268S sporozoite, a defect not rescued by coinfection with wild type parasites. Furthermore, despite uniformly successful transmission of wild type parasites from An. stephensi to FRG NOD huHep mice bearing human hepatocytes and erythrocytes, multiple attempts with Y268S-fed mosquitoes failed: there was no evidence of parasites in mouse tissues by microscopy, in vitro culture, or PCR. These studies confirm a severe-to-lethal fitness cost of clinically relevant atovaquone-resistant P. falciparum in the mosquito, and they significantly lessen the likelihood of their transmission in the field.

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“…Antimalarial drug resistance of malaria parasites is acquired by mutations or duplications in target genes, which can confer reduced drug susceptibility. Up to now, multiple genes associated with antimalarial drug resistances have been identified and major mutations inducing the resistances have been characterized [ 3 , 4 , 5 ]. The Great Mekong Subregion (GMS) has been recognized as a breeding hub for antimalarial drug resistant malaria parasites.…”

Section: Introductionmentioning

confidence: 99%

“…The unique geographical location of Myanmar, which connects GMS and South Asia, has also emphasized its importance as a bridge to spread antimalarial drug resistant parasites from GMS to South Asia countries [ 16 ]. Molecular analysis of antimalarial drug resistance markers has been validated as one effective tool for surveillance of resistance [ 3 , 4 , 5 ]. These markers serve as valuable molecular blueprints for mapping drug resistance status and planning malaria control measures [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular Profiles of Multiple Antimalarial Drug Resistance Markers in Plasmodium falciparum and Plasmodium vivax in the Mandalay Region, Myanmar

et al. 2022

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Emergence and spreading of antimalarial drug resistant malaria parasites are great hurdles to combating malaria. Although approaches to investigate antimalarial drug resistance status in Myanmar malaria parasites have been made, more expanded studies are necessary to understand the nationwide aspect of antimalarial drug resistance. In the present study, molecular epidemiological analysis for antimalarial drug resistance genes in Plasmodium falciparum and P. vivax from the Mandalay region of Myanmar was performed. Blood samples were collected from patients infected with P. falciparum and P. vivax in four townships around the Mandalay region, Myanmar in 2015. Partial regions flanking major mutations in 11 antimalarial drug resistance genes, including seven genes (pfdhfr, pfdhps, pfmdr-1, pfcrt, pfk13, pfubp-1, and pfcytb) of P. falciparum and four genes (pvdhfr, pvdhps, pvmdr-1, and pvk12) of P. vivax were amplified, sequenced, and overall mutation patterns in these genes were analyzed. Substantial levels of mutations conferring antimalarial drug resistance were detected in both P. falciparum and P. vivax isolated in Mandalay region of Myanmar. Mutations associated with sulfadoxine-pyrimethamine resistance were found in pfdhfr, pfdhps, pvdhfr, and pvdhps of Myanmar P. falciparum and P. vivax with very high frequencies up to 90%. High or moderate levels of mutations were detected in genes such as pfmdr-1, pfcrt, and pvmdr-1 associated with chloroquine resistance. Meanwhile, low frequency mutations or none were found in pfk13, pfubp-1, pfcytb, and pvk12 of the parasites. Overall molecular profiles for antimalarial drug resistance genes in malaria parasites in the Mandalay region suggest that parasite populations in the region have substantial levels of mutations conferring antimalarial drug resistance. Continuous monitoring of mutations linked with antimalarial drug resistance is necessary to provide useful information for policymakers to plan for proper antimalarial drug regimens to control and eliminate malaria in the country.

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Genomic Approaches to Drug Resistance in Malaria

Cited by 15 publications

References 154 publications

Genetic surveillance for monitoring the impact of drug use on Plasmodium falciparum populations

Genetic surveillance for monitoring the impact of drug use on Plasmodium falciparum populations

Transmissibility of clinically relevant atovaquone-resistantPlasmodium falciparumby anopheline mosquitoes

Molecular Profiles of Multiple Antimalarial Drug Resistance Markers in Plasmodium falciparum and Plasmodium vivax in the Mandalay Region, Myanmar

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