Dihydrofolate-Reductase Mutations in Plasmodium knowlesi Appear Unrelated to Selective Drug Pressure from Putative Human-To-Human Transmission in Sabah, Malaysia.

التفاصيل البيبلوغرافية
العنوان:	Dihydrofolate-Reductase Mutations in Plasmodium knowlesi Appear Unrelated to Selective Drug Pressure from Putative Human-To-Human Transmission in Sabah, Malaysia.
المؤلفون:	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
المصدر:	PLoS ONE, Vol 11, Iss 3, p e0149519 (2016)
بيانات النشر:	Public Library of Science (PLoS), 2016.
سنة النشر:	2016
المجموعة:	LCC:Medicine LCC:Science
مصطلحات موضوعية:	Medicine, Science
الوصف:	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.
نوع الوثيقة:	article
وصف الملف:	electronic resource
اللغة:	English
تدمد:	1932-6203
Relation:	http://europepmc.org/articles/PMC4773021?pdf=render; https://doaj.org/toc/1932-6203
DOI:	10.1371/journal.pone.0149519
URL الوصول:	https://doaj.org/article/12492413a4594b4f97c7f0bde069e223
رقم الانضمام:	edsdoj.12492413a4594b4f97c7f0bde069e223
قاعدة البيانات:	Directory of Open Access Journals

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الوصف
تدمد:	19326203
DOI:	10.1371/journal.pone.0149519