Dihydrofolate-reductase mutations in Plasmodium knowlesi appear unrelated to selective drug pressure from putative human-to-human transmission in Sabah, Malaysia
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 (H-H) transmission is occurring naturally. We sought evidence of drug selection pressure from the antimalarial sulfadoxin...
| Principais autores: | , , , , , , , , , , , , , , , |
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| Formato: | Journal Article |
| Idioma: | English |
| Publicado em: |
2018
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| Acesso em linha: | https://hdl.handle.net/10356/87597 http://hdl.handle.net/10220/46773 |
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| author | Yeo, Tsin Wen Auburn, Sarah Anstey, Nicholas M. 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 |
| author2 | Tsuboi, Takafumi |
| author_facet | Tsuboi, Takafumi Yeo, Tsin Wen Auburn, Sarah Anstey, Nicholas M. 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 |
| author_sort | Yeo, Tsin Wen |
| collection | NTU |
| description | 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 (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. 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 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. Conclusion: Although moderate diversity was observed in pkdhfr in Sabah, there was no evidence this reflected selective antifolate drug pressure in humans. |
| first_indexed | 2024-10-01T06:39:29Z |
| format | Journal Article |
| id | ntu-10356/87597 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T06:39:29Z |
| publishDate | 2018 |
| record_format | dspace |
| spelling | ntu-10356/875972022-02-16T16:26:26Z Dihydrofolate-reductase mutations in Plasmodium knowlesi appear unrelated to selective drug pressure from putative human-to-human transmission in Sabah, Malaysia Yeo, Tsin Wen Auburn, Sarah Anstey, Nicholas M. 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 Tsuboi, Takafumi Lee Kong Chian School of Medicine (LKCMedicine) Malaria DRNTU::Science::Medicine Plasmodium Knowlesi 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 (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. 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 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. Conclusion: Although moderate diversity was observed in pkdhfr in Sabah, there was no evidence this reflected selective antifolate drug pressure in humans. Published version 2018-12-03T07:04:49Z 2019-12-06T16:45:19Z 2018-12-03T07:04:49Z 2019-12-06T16:45:19Z 2016 Journal Article Grigg, M. J., Barber, B. E., Marfurt, J., Imwong, M., William, T., Bird, E., . . . Anstey, N. M. (2016). Dihydrofolate-reductase mutations in Plasmodium knowlesi appear unrelated to selective drug pressure from putative human-to-human transmission in Sabah, Malaysia. PLOS ONE, 11(3), e0149519-. doi:10.1371/journal.pone.0149519 https://hdl.handle.net/10356/87597 http://hdl.handle.net/10220/46773 10.1371/journal.pone.0149519 26930493 en PLOS ONE © 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. 19 p. application/pdf |
| spellingShingle | Malaria DRNTU::Science::Medicine Plasmodium Knowlesi Yeo, Tsin Wen Auburn, Sarah Anstey, Nicholas M. 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 Dihydrofolate-reductase mutations in Plasmodium knowlesi appear unrelated to selective drug pressure from putative human-to-human transmission in Sabah, Malaysia |
| title | 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_short | 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 |
| topic | Malaria DRNTU::Science::Medicine Plasmodium Knowlesi |
| url | https://hdl.handle.net/10356/87597 http://hdl.handle.net/10220/46773 |
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