Changing Prevalence of Potential Mediators of Aminoquinoline, Antifolate, and Artemisinin Resistance Across Uganda

The Journal of Infectious Diseases, Journal Year: 2020, Volume and Issue: 223(6), P. 985 - 994

Published: Oct. 27, 2020

In Uganda, artemether-lumefantrine is recommended for malaria treatment and sulfadoxine-pyrimethamine chemoprevention during pregnancy, but drug resistance may limit efficacies. Genetic polymorphisms associated with sensitivities to key drugs were characterized in samples collected from 16 sites across Uganda 2018 2019 by ligase detection reaction fluorescent microsphere, molecular inversion probe, dideoxy sequencing, quantitative polymerase chain assays. Considering transporter aminoquinolines, the prevalence of Plasmodium falciparum chloroquine (PfCRT) 76T decreased, varied markedly between (0-46% 2018; 0-23% 2019); additional PfCRT plasmepsin-2/3 amplifications elsewhere piperaquine not seen. For P. multidrug protein 1, 86Y mutation was absent at all sites, 1246Y had ≤20% 14 gene amplification mutations high-level resistance, prevalences dihydrofolate reductase 164L (up 80%) dihydropteroate synthase 581G 67%) high multiple sites. kelch propeller domain artemisinin delayed clearance, 469Y 675V has increased northern 23% 41%, respectively). We demonstrate concerning spread that efficacies antimalarial drugs.

Language: Английский

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Plasmodium falciparum is evolving to escape malaria rapid diagnostic tests in Ethiopia

Nature Microbiology, Journal Year: 2021, Volume and Issue: 6(10), P. 1289 - 1299

Published: Sept. 27, 2021

In Africa, most rapid diagnostic tests (RDTs) for falciparum malaria recognize histidine-rich protein 2 antigen. Plasmodium parasites lacking (pfhrp2) and 3 (pfhrp3) genes escape detection by these RDTs, but it is not known whether deletions confer sufficient selective advantage to drive population expansion. By studying blood samples from a cohort of 12,572 participants enroled in prospective, cross-sectional survey along Ethiopia's borders with Eritrea, Sudan South using PCR, an ultrasensitive bead-based immunoassay antigen next-generation sequencing, we estimate that 2-based RDTs would miss 9.7% (95% confidence interval 8.5-11.1) P. cases owing pfhrp2 deletion. We applied molecular inversion probe-targeted deep sequencing approach identify distinct subtelomeric deletion patterns well-established pfhrp3 uncover recent expansion singular all regions sampled. propose model which have arisen independently multiple times, followed strong positive selection RDT-based test-and-treatment. Existing strategies need be urgently reconsidered Ethiopia, improved surveillance needed throughout the Horn Africa.

Language: Английский

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Evolution of Partial Resistance to Artemisinins in Malaria Parasites in Uganda

New England Journal of Medicine, Journal Year: 2023, Volume and Issue: 389(8), P. 722 - 732

Published: Aug. 23, 2023

Partial resistance of Plasmodium falciparum to the artemisinin component artemisinin-based combination therapies, most important malaria drugs, emerged in Southeast Asia and now threatens East Africa. resistance, which manifests as delayed clearance after therapy, is mediated principally by mutations kelch protein K13 (PfK13). Limited longitudinal data are available on emergence spread We performed annual surveillance among patients who presented with uncomplicated at 10 16 sites across Uganda from 2016 through 2022. sequenced gene encoding 13 (pfk13) analyzed relatedness using molecular methods. assessed metrics longitudinally eight Ugandan districts 2014 2021. By 2021-2022, prevalence parasites validated or candidate markers reached more than 20% 11 where was conducted. The PfK13 469Y 675V were seen far northern 2016-2017 increased thereafter, reaching a combined 54% much Uganda, other regions. 469F mutation 38 40% one district southwestern 2021-2022. 561H mutation, previously described Rwanda, first 2021, 23% 441L 12 three western Genetic analysis indicated local mutant independent those Asia. observed predominantly areas effective control had been discontinued transmission unstable. Data showed partial artemisinins multiple geographic locations, increasing regional over time. (Funded National Institutes Health.).

Language: Английский

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Advances and opportunities in malaria population genomics

Nature Reviews Genetics, Journal Year: 2021, Volume and Issue: 22(8), P. 502 - 517

Published: April 8, 2021

Language: Английский

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Plasmodium falciparum resistant to artemisinin and diagnostics have emerged in Ethiopia

Nature Microbiology, Journal Year: 2023, Volume and Issue: 8(10), P. 1911 - 1919

Published: Aug. 28, 2023

Abstract Diagnosis and treatment of Plasmodium falciparum infections are required for effective malaria control pre-requisites elimination efforts; hence we need to monitor emergence, evolution spread drug- diagnostics-resistant parasites. We deep sequenced key drug-resistance mutations 1,832 SNPs in the parasite genomes 609 cases collected during a diagnostic-resistance surveillance study Ethiopia. found that 8.0% (95% CI 7.0–9.0) were caused by P. carrying candidate artemisinin partial-resistance kelch13 ( K13 ) 622I mutation, which was less common diagnostic-resistant parasites mediated histidine-rich proteins 2 3 pfhrp2/3 deletions than wild-type P = 0.03). Identity-by-descent analyses showed significantly more related each other wild type < 0.001), consistent with recent expansion this mutation. Pfhrp2/3- deleted also highly related, evidence clonal transmissions at district level. Of concern, 8.2% carried deletions. Close monitoring combined is needed.

Language: Английский

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Decreased susceptibility of Plasmodium falciparum to both dihydroartemisinin and lumefantrine in northern Uganda

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Oct. 26, 2022

Artemisinin partial resistance may facilitate selection of Plasmodium falciparum resistant to combination therapy partner drugs. We evaluated 99 P. isolates collected in 2021 from northern Uganda, where resistance-associated PfK13 C469Y and A675V mutations have emerged, eastern these are uncommon. With the ex vivo ring survival assay, with 469Y mutation (median 7.3% for mutant, 2.5% mixed, 1.4% wild type) and/or Pfcoronin or falcipain-2a, had significantly greater survival; all >5% at least one proteins. growth inhibition assays, susceptibility lumefantrine IC50 14.6 vs. 6.9 nM, p < 0.0001) dihydroartemisinin (2.3 1.5 = 0.003) was decreased Uganda; 14/49 0/38 > 20 nM (p 0.0002). Targeted sequencing 819 2015-21 identified multiple polymorphisms associated altered drug susceptibility, notably 6 × 10-8) PfCRT chloroquine 1 10-20). Our results raise concern regarding activity artemether-lumefantrine, first-line antimalarial Uganda.

Language: Английский

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Flexible and cost-effective genomic surveillance of P. falciparum malaria with targeted nanopore sequencing

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Feb. 15, 2024

Abstract Genomic surveillance of Plasmodium falciparum malaria can provide policy-relevant information about antimalarial drug resistance, diagnostic test failure, and the evolution vaccine targets. Yet large low complexity genome P. complicates development genomic methods, while resource constraints in endemic regions limit their deployment. Here, we demonstrate an approach for targeted nanopore sequencing from dried blood spots (DBS) that enables cost-effective low-resource settings. We release software facilitates flexible design amplicon panels use this to two target . The generate 3–4 kbp reads eight sixteen targets respectively, covering key drug-resistance associated genes, antigens, polymorphic markers csp validate our on mock field samples, demonstrating robust coverage, accurate variant calls within coding sequences, ability explore within-sample diversity detect deletions underlying rapid failure.

Language: Английский

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Antimalarial Drug Resistance and Implications for the WHO Global Technical Strategy

Current Epidemiology Reports, Journal Year: 2021, Volume and Issue: 8(2), P. 46 - 62

Published: March 14, 2021

Language: Английский

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Country wide surveillance reveals prevalent artemisinin partial resistance mutations with evidence for multiple origins and expansion of high level sulfadoxine-pyrimethamine resistance mutations in northwest Tanzania

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 8, 2023

Abstract Background Emergence of artemisinin partial resistance (ART-R) in Plasmodium falciparum is a growing threat to the efficacy combination therapies (ACT) and efforts for malaria elimination. The emergence Kelch13 (K13) R561H Rwanda raised concern about impact neighboring Tanzania. In addition, regional over affecting sulfadoxine-pyrimethamine (SP), which used chemoprevention strategies, high. Methods To enhance longitudinal monitoring, Molecular Surveillance Malaria Tanzania (MSMT) project was launched 2020 with goal assessing mapping antimalarial resistance. Community clinic samples were assessed polymorphisms using molecular inversion probe platform. Findings Genotyping 6,278 collected countrywide 2021 revealed focus K13 561H mutants northwestern (Kagera) prevalence 7.7% (50/649). A small number (about 1%) found as far 800 km away Tabora, Manyara, Njombe. Genomic analysis suggests some these parasites are highly related isolates 2015, supporting spread 561H. However, novel haplotype also observed, likely indicating second origin region. Other validated (622I 675V) identified. high drug identified Kagera dihydrofolate reductase 164L 15% (80/526). Interpretation These findings demonstrate mutation entrenched region that multiple origins ART-R, similar what seen Southeast Asia, have occurred. Mutations associated levels SP increasing. results raise concerns long-term antimalarials Funding This study funded by Bill Melinda Gates Foundation National Institutes Health. Research Context Evidence before this We did literature search via PubMed research articles published from January 2014 October 2023 term “Africa” “Artemisinin resistance” linked “R561H” or “A675V” “R622I”, returning 32 studies. shows establishment three kelch13 mutations Africa. Large studies 675V Uganda 622I Ethiopia defined mutations. limited data available recent Great Lakes East particular, detailed regions border not been carried out since detected Rwanda. needed control programs define implement strategies controlling ART-R Africa, potential global public health disaster obstacle ongoing elimination strategies. Added value reports first large-scale Tanzania, on bordering reached frequency area. Using P. positive sequenced probes (MIPs), we show has become frequent districts Importantly, provide evidence separate different extended around independent emergences occurred within last two decades Asia. Implications all highlight that, other parts can expect continue it highlights need be watchful new beyond existing resistant parasite lineages. appears now well established areas Eastern Intensive prevent monitoring partner affected will critical preventing further reversal support progress targets 2023.

Language: Английский

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High frequency of artemisinin partial resistance mutations in the great lake region revealed through rapid pooled deep sequencing

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 1, 2024

Abstract In Africa, the first Plasmodium falciparum Kelch13 (K13) artemisinin partial resistance mutation 561H was detected and validated in Rwanda. Surveillance to better define extent of emergence Rwanda neighboring countries as other mutations arise East Africa is critical. We employ a novel scheme liquid blood drop preservation combined with pooled sequencing provide cost-effective rapid assessment frequencies at multiple collection sites across countries. Malaria-positive samples (n=5,465) were collected from 39 health facilities Rwanda, Uganda, Tanzania, Democratic Republic Congo (DRC) between May 2022 March 2023 sequenced 199 pools. K13 675V 90% 65% an average frequency 19.0% (0-54.5%) 5.0% (0-35.5%), respectively. had high while it absent DRC although seen low frequency. Conceringly candidate observed: 441L, 449A, 469F co-occurred suggesting they are arising under same pressures. Other markers associated artemether-lumefantrine common: P. multidrug protein 1 N86 98.0% 184F 47.0% (0-94.3%) chloroquine transporter 76T 14.7% (0-58.6%). Additionally, sulfadoxine-pyrimethamine-associated show frequencies. Overall, rapidly expanding region further endangering control efforts potential engendering partner drug resistance.

Language: Английский

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