Dihydrofolate-reductase mutations in plasmodium knowlesi appear unrelated to selective drug pressure from putative human-to-human transmission in Sabah, Malaysia
© 2016 Grigg et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background Malaria caused by zoonotic Plasmo...
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th-mahidol.409702019-03-14T15:01:54Z Dihydrofolate-reductase mutations in plasmodium knowlesi appear unrelated to selective drug pressure from putative human-to-human transmission in Sabah, Malaysia Matthew J. Grigg Bridget E. Barber Jutta Marfurt Mallika Imwong Timothy William Elspeth Bird Kim A. Piera Ammar Aziz Usa Boonyuen Christopher J. Drakeley Jonathan Cox Nicholas J. White Qin Cheng Tsin W. Yeo Sarah Auburn Nicholas M. Anstey Menzies School of Health Research Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit Mahidol University Queen Elizabeth Hospital Jesselton Medical Centre London School of Hygiene & Tropical Medicine Royal Darwin Hospital Nanyang Technological University Australian Army Malaria Institute QIMR Berghofer Medical Research Institute Agricultural and Biological Sciences Biochemistry, Genetics and Molecular Biology © 2016 Grigg et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background Malaria caused by zoonotic Plasmodium knowlesi is an emerging threat in Eastern Malaysia. Despite demonstrated vector competency, it is unknown whether human-to-human (HH) 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. Methods 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. Results 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 doublemutants. 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. Conclusion Although moderate diversity was observed in pkdhfr in Sabah, there was no evidence this reflected selective antifolate drug pressure in humans. 2018-12-11T02:01:28Z 2019-03-14T08:01:54Z 2018-12-11T02:01:28Z 2019-03-14T08:01:54Z 2016-03-01 Article PLoS ONE. Vol.11, No.3 (2016) 10.1371/journal.pone.0149519 19326203 2-s2.0-84962243417 https://repository.li.mahidol.ac.th/handle/123456789/40970 Mahidol University SCOPUS https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84962243417&origin=inward |
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Agricultural and Biological Sciences Biochemistry, Genetics and Molecular Biology Matthew J. Grigg Bridget E. Barber Jutta Marfurt Mallika Imwong Timothy William Elspeth Bird Kim A. Piera Ammar Aziz Usa Boonyuen Christopher J. Drakeley Jonathan Cox Nicholas J. White Qin Cheng Tsin W. Yeo Sarah Auburn Nicholas M. Anstey Dihydrofolate-reductase mutations in plasmodium knowlesi appear unrelated to selective drug pressure from putative human-to-human transmission in Sabah, Malaysia |
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© 2016 Grigg et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background Malaria caused by zoonotic Plasmodium knowlesi is an emerging threat in Eastern Malaysia. Despite demonstrated vector competency, it is unknown whether human-to-human (HH) 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. Methods 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. Results 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 doublemutants. 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. Conclusion Although moderate diversity was observed in pkdhfr in Sabah, there was no evidence this reflected selective antifolate drug pressure in humans. |
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Menzies School of Health Research |
author_facet |
Menzies School of Health Research Matthew J. Grigg Bridget E. Barber Jutta Marfurt Mallika Imwong Timothy William Elspeth Bird Kim A. Piera Ammar Aziz Usa Boonyuen Christopher J. Drakeley Jonathan Cox Nicholas J. White Qin Cheng Tsin W. Yeo Sarah Auburn Nicholas M. Anstey |
format |
Article |
author |
Matthew J. Grigg Bridget E. Barber Jutta Marfurt Mallika Imwong Timothy William Elspeth Bird Kim A. Piera Ammar Aziz Usa Boonyuen Christopher J. Drakeley Jonathan Cox Nicholas J. White Qin Cheng Tsin W. Yeo Sarah Auburn Nicholas M. Anstey |
author_sort |
Matthew J. Grigg |
title |
Dihydrofolate-reductase mutations in plasmodium knowlesi appear unrelated to selective drug pressure from putative human-to-human transmission in Sabah, Malaysia |
title_short |
Dihydrofolate-reductase mutations in plasmodium knowlesi appear unrelated to selective drug pressure from putative human-to-human transmission in Sabah, Malaysia |
title_full |
Dihydrofolate-reductase mutations in plasmodium knowlesi appear unrelated to selective drug pressure from putative human-to-human transmission in Sabah, Malaysia |
title_fullStr |
Dihydrofolate-reductase mutations in plasmodium knowlesi appear unrelated to selective drug pressure from putative human-to-human transmission in Sabah, Malaysia |
title_full_unstemmed |
Dihydrofolate-reductase mutations in plasmodium knowlesi appear unrelated to selective drug pressure from putative human-to-human transmission in Sabah, Malaysia |
title_sort |
dihydrofolate-reductase mutations in plasmodium knowlesi appear unrelated to selective drug pressure from putative human-to-human transmission in sabah, malaysia |
publishDate |
2018 |
url |
https://repository.li.mahidol.ac.th/handle/123456789/40970 |
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1763496864024363008 |