Prevalence of Plasmodium falciparum delayed clearance associated polymorphisms in adaptor protein complex 2 mu subunit (pfap2mu) and ubiquitin specific protease 1 (pfubp1) genes in Ghanaian isolates

Adams, Tryphena; Ennuson, Nana Aba; Quashie, Neils B; Futagbi, Godfred; Matrevi, Sena; Hagan, Charles Oheneba; Abuaku, Benjamin; Koram, Kwadwo A.; Duah, Nancy O.

doi:10.1186/s13071-018-2762-3

Cited by 37 publications

(39 citation statements)

References 21 publications

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“…However, there have been increasing reports of ACT failures, or delayed parasite clearance within Africa suggesting the need to investigate the factors that might be responsible (8,9).…”

Section: Introductionmentioning

confidence: 99%

Molecular detection of drug resistant polymorphisms in Plasmodium falciparum isolates from Southwest, Nigeria.

Tola

Ajibola

Idowu

et al. 2020

Preprint

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Objective Nigeria bears 25% of global malaria burden despite concerted efforts towards its control and elimination. The emergence of drug resistance to first line drugs, artemisinin combination therapies (ACTs), indicates an urgent need for continuous molecular surveillance of drug resistance especially in high burden countries where drug interventions are heavily relied on. This study describes mutations in Plasmodium falciparum genes associated with drug resistance in malaria; Pfk1 3, Pfmdr1 , PfATPase6 and Pfcrt in isolates obtained from 83 symptomatic malaria patients between 1-61 years old from Lagos, a Mega city in South-west Nigeria. Results Two Pfmdr 1, N86 and Y184 variants were present at a prevalence of 56% and 13.25% of isolates respectively. There was one synonymous (S679S) and two non-synonymous (M699V, S769M) mutations in the Pfatp6 gene, while Pfcrt genotype (CVIET), had a prevalence of 45%. The Pfk13 C580Y mutant allele was detected by allelic discrimination in two samples with mixed genotypes. Pfk13 C580Y in west Africa is rare and this result calls for robust and larger scale surveillance of artemisinin resistance associated polymorphisms and delayed clearance phenotype in Nigeria.

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“…However, there have been increasing reports of ACT failures, or delayed parasite clearance within Africa suggesting the need to investigate the factors that might be responsible (8,9).…”

Section: Introductionmentioning

confidence: 99%

Molecular detection of drug resistant polymorphisms in Plasmodium falciparum isolates from Southwest, Nigeria.

Tola

Ajibola

Idowu

et al. 2020

Preprint

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“…Recently, these mutations have been introduced into UBP-1 in P. falciparum, and the V2721F equivalent has been shown to associate with increased DHA RSA survival with no CQ resistance phenotype, whereas the V2728F orthologue appeared to have no ART or CQ resistance profiles (15). More interestingly, UBP-1 mutation variants have been associated with decreased effectiveness of ARTs in Africa and some parts of Asia (16)(17)(18)(19).…”

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confidence: 99%

Experimentally Engineered Mutations in a Ubiquitin Hydrolase, UBP-1, Modulate In Vivo Susceptibility to Artemisinin and Chloroquine in Plasmodium berghei

Simwela

Hughes

Roberts

et al. 2020

Antimicrob Agents Chemother

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As resistance to artemisinins (current frontline drugs in malaria treatment) emerges in Southeast Asia, there is an urgent need to identify the genetic determinants and understand the molecular mechanisms underpinning such resistance. Such insights could lead to prospective interventions to contain resistance and prevent the eventual spread to other regions where malaria is endemic. Reduced susceptibility to artemisinin in Southeast Asia has been primarily linked to mutations in the Plasmodium falciparum Kelch-13 gene, which is currently widely recognized as a molecular marker of artemisinin resistance. However, two mutations in a ubiquitin hydrolase, UBP-1, have been previously associated with reduced artemisinin susceptibility in a rodent model of malaria, and some cases of UBP-1 mutation variants associated with artemisinin treatment failure have been reported in Africa and SEA. In this study, we employed CRISPR-Cas9 genome editing and preemptive drug pressures to test these artemisinin susceptibility-associated mutations in UBP-1 in Plasmodium berghei sensitive lines in vivo. Using these approaches, we show that the V2721F UBP-1 mutation results in reduced artemisinin susceptibility, while the V2752F mutation results in resistance to chloroquine (CQ) and moderately impacts tolerance to artemisinins. Genetic reversal of the V2752F mutation restored chloroquine sensitivity in these mutant lines, whereas simultaneous introduction of both mutations could not be achieved and appears to be lethal. Interestingly, these mutations carry a detrimental growth defect, which would possibly explain their lack of expansion in natural infection settings. Our work provides independent experimental evidence on the role of UBP-1 in modulating parasite responses to artemisinin and chloroquine under in vivo conditions.

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“…Studies on the molecular markers of ART resistance showed increased P. falciparum multidrug resistance gene (pfmdr1) copy number in 18% of isolates and an increasing trend in the prevalence of haplotype pfmdr1 N86-F184-D1246 (linked to AL resistance) from 2003 to 2010 (22). In addition, the P. falciparum adaptor protein complex 2 gene (pfap2mu) S106N and ubiquitin specific protease 1 gene (pfubp1) E1528D and D1525E mutations, which have been linked to the delayed clearance of parasites to ACT in Kenya and recurrent imported malaria in Britain, were observed in 7.4%, 7.4%, and 4.9%, respectively, of Ghanaian parasites (23)(24)(25). This is indicative of the possibility of subtle levels of ART resistance in circulating parasites.…”

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confidence: 99%

Plasmodium falciparum Kelch Propeller Polymorphisms in Clinical Isolates from Ghana from 2007 to 2016

Matrevi

Opoku-Agyeman

Quashie

et al. 2019

Antimicrob Agents Chemother

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The continuous surveillance of polymorphisms in the kelch propeller domain of Plasmodium falciparum from Africa is important for the discovery of the actual markers of artemisinin resistance in the region. The information on the markers is crucial for control strategies involving chemotherapy and chemoprophylaxis for residents and nonimmune travelers to the country. Polymorphisms in the kelch propeller domain of Ghanaian malaria parasites from three different ecological zones at several time periods were assessed. A total of 854 archived samples (2007 to 2016) collected from uncomplicated malaria patients aged ≤9 years old from 10 sentinel sites were used. Eighty-four percent had wild-type sequences (PF3D7_1343700), while many of the mutants had mostly nonsynonymous mutations clustered around codons 404 to 650. Variants with different amino acid changes of the codons associated with artemisinin (ART) resistance validated markers were observed in Ghanaian isolates: frequencies for I543I, I543S, I543V, R561P, R561R, and C580V were 0.12% each and 0.6% for R539I. Mutations reported from African parasites, A578S (0.23%) and Q613L (0.23%), were also observed. Three persisting nonsynonymous (NS) mutations, N599Y (0.005%), K607E (0.004%), and V637G (0.004%), were observed in 3 of the 5 time periods nationally. The presence of variants of the validated markers of artemisinin resistance as well as persisting polymorphisms after 14 years of artemisinin-based combination therapy use argues for continuous surveillance of the markers. The molecular markers of artemisinin resistance and the observed variants will be monitored subsequently as part of ongoing surveillance of antimalarial drug efficacy/resistance studies in the country.

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Prevalence of Plasmodium falciparum delayed clearance associated polymorphisms in adaptor protein complex 2 mu subunit (pfap2mu) and ubiquitin specific protease 1 (pfubp1) genes in Ghanaian isolates

Cited by 37 publications

References 21 publications

Molecular detection of drug resistant polymorphisms in Plasmodium falciparum isolates from Southwest, Nigeria.

Molecular detection of drug resistant polymorphisms in Plasmodium falciparum isolates from Southwest, Nigeria.

Experimentally Engineered Mutations in a Ubiquitin Hydrolase, UBP-1, Modulate In Vivo Susceptibility to Artemisinin and Chloroquine in Plasmodium berghei

Plasmodium falciparum Kelch Propeller Polymorphisms in Clinical Isolates from Ghana from 2007 to 2016

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