Please use this identifier to cite or link to this item: http://docs.prosentient.com.au/prosentientjspui/handle/1/10889
Title: Dihydrofolate-Reductase Mutations in Plasmodium knowlesi Appear Unrelated to Selective Drug Pressure from Putative Human-To-Human Transmission in Sabah, Malaysia.
Authors: Grigg, Matthew J
Barber, Bridget E
Marfurt, Jutta
Imwong, Mallika
William, Timothy
Bird, Elspeth
Piera, Kim A
Aziz, Ammar
Boonyuen, Usa
Drakeley, Christopher J
Cox, Jonathan
White, Nicholas J
Cheng, Qin
Yeo, Tsin W
Auburn, Sarah
Anstey, Nicholas M
Affiliation: Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia.. Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, Kota Kinabalu, Sabah, Malaysia..
Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia.. Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, Kota Kinabalu, Sabah, Malaysia..
Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia..
Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.. Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand..
Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, Kota Kinabalu, Sabah, Malaysia.. Clinical Research Centre, Queen Elizabeth Hospital, Sabah, Malaysia.. Jesselton Medical Centre, Kota Kinabalu, Sabah, Malaysia..
Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, Kota Kinabalu, Sabah, Malaysia..
Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia..
Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia..
Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand..
Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom..
Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom..
Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand..
Australian Army Malaria Institute, Brisbane, Australia.. Clinical Tropical Medicine, Queensland Institute of Medical Research, Brisbane, Australia..
Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia.. Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, Kota Kinabalu, Sabah, Malaysia.. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore..
Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia..
Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia.. Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, Kota Kinabalu, Sabah, Malaysia.. Royal Darwin Hospital, Darwin, Northern Territory, Australia..
Issue Date: 2016
Citation: PloS one 2016; 11(3): e0149519
Abstract: Malaria 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. The 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. Fourteen 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. Although moderate diversity was observed in pkdhfr in Sabah, there was no evidence this reflected selective antifolate drug pressure in humans.
URI: http://docs.prosentient.com.au/prosentientjspui/handle/1/10889
DOI: 10.1371/journal.pone.0149519
Type: Journal Article
Research Support, Non-U.S. Gov't
Subjects: Adolescent
Adult
Aged
Aged, 80 and over
Antimalarials
Child
Child, Preschool
Drug Resistance
Female
Folic Acid Antagonists
Humans
Infant
Malaria
Malaysia
Male
Middle Aged
Molecular Docking Simulation
Plasmodium knowlesi
Pyrimethamine
Tetrahydrofolate Dehydrogenase
Young Adult
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