ArticlePloS one2016
Dihydrofolate-Reductase Mutations in Plasmodium knowlesi Appear Unrelated to Selective Drug Pressure from Putative Human-To-Human Transmission in Sabah, Malaysia.
Article in PloS one, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers, 1 of them a synthesis that pooled it.
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Who cites it
12 citing papers in PubMed, 1 synthesis or guideline pooled it, 25 citations in OpenAlex.
- Is there evidence of sustained human-mosquito-human transmission of the zoonotic malaria Plasmodium knowlesi? A systematic literature review.Malaria journal · 2022Pooled it
- Genomic epidemiology of Plasmodium knowlesi reveals putative genetic drivers of adaptation in Malaysia.PLoS neglected tropical diseases · 2025Article
- Limited Polymorphism in the Dihydrofolate Reductase (dhfr) and dihydropteroate synthase genes (dhps) of Plasmodium knowlesi isolate from Thailand.Acta tropica · 2023Article
- Quantification of parasite clearance in Plasmodium knowlesi infections.Malaria journal · 2023Article
- Plasmodium knowlesi: the game changer for malaria eradication.Malaria journal · 2022Review
- Genetic population of Plasmodium knowlesi during pre-malaria elimination in Thailand.Malaria journal · 2021Article
- Clinical management of Plasmodium knowlesi malaria.Advances in parasitology · 2021Review
- Plasmodium knowlesi detection methods for human infections-Diagnosis and surveillance.Advances in parasitology · 2021Article
- Knowlesi malaria: Human risk factors, clinical spectrum, and pathophysiology.Advances in parasitology · 2021Article
- Asymptomatic Natural Human Infections With the Simian Malaria Parasites Plasmodium cynomolgi and Plasmodium knowlesi.The Journal of infectious diseases · 2019Article
- Review
- Transfusion-transmitted severe Plasmodium knowlesi malaria in a splenectomized patient with beta-thalassaemia major in Sabah, Malaysia: a case report.Malaria journal · 2016Article
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Authors and funding
16 authors at 7 institutions in 5 countries.
Funding
Abstract
backgroundMalaria caused by zoonotic Plasmodium knowlesi is an emerging threat in Eastern Malaysia. Despite demonstrated vector competency, it is unknown whether human-to-human (H-H) transmission is occurring naturally. We sought evidence of drug selection pressure from the antimalarial sulfadoxine-pyrimethamine (SP) as a potential marker of H-H transmission.
methodsThe P. knowlesi dihdyrofolate-reductase (pkdhfr) gene was sequenced from 449 P. knowlesi malaria cases from Sabah (Malaysian Borneo) and genotypes evaluated for association with clinical and epidemiological factors. Homology modelling using the pvdhfr template was used to assess the effect of pkdhfr mutations on the pyrimethamine binding pocket.
resultsFourteen non-synonymous mutations were detected, with the most common being at codon T91P (10.2%) and R34L (10.0%), resulting in 21 different genotypes, including the wild-type, 14 single mutants, and six double mutants. One third of the P. knowlesi infections were with pkdhfr mutants; 145 (32%) patients had single mutants and 14 (3%) had double-mutants. In contrast, among the 47 P. falciparum isolates sequenced, three pfdhfr genotypes were found, with the double mutant 108N+59R being fixed and the triple mutants 108N+59R+51I and 108N+59R+164L occurring with frequencies of 4% and 8%, respectively. Two non-random spatio-temporal clusters were identified with pkdhfr genotypes. There was no association between pkdhfr mutations and hyperparasitaemia or malaria severity, both hypothesized to be indicators of H-H transmission. The orthologous loci associated with resistance in P. falciparum were not mutated in pkdhfr. Subsequent homology modelling of pkdhfr revealed gene loci 13, 53, 120, and 173 as being critical for pyrimethamine binding, however, there were no mutations at these sites among the 449 P. knowlesi isolates.
conclusionAlthough moderate diversity was observed in pkdhfr in Sabah, there was no evidence this reflected selective antifolate drug pressure in humans.
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