ArticleProceedings of the National Academy of Sciences of the United States of America2011
Malaria antifolate resistance with contrasting Plasmodium falciparum dihydrofolate reductase (DHFR) polymorphisms in humans and Anopheles mosquitoes.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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41 citing papers in PubMed, 68 citations in OpenAlex.
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- Tracking antimalarial drug resistance using mosquito blood meals: a cross-sectional study.The Lancet. Microbe · 2023Article
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- Temporal trends in molecular markers of drug resistance in Plasmodium falciparum in human blood and profiles of corresponding resistant markers in mosquito oocysts in Asembo, western Kenya.Malaria journal · 2022Article
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- Molecular Surveillance for Imported Antimicrobial Resistant Plasmodium falciparum, Ontario, Canada.Emerging infectious diseases · 2022Article
- Longitudinal impact of asymptomatic malaria/HIV-1 co-infection onFrontiers in cellular and infection microbiology · 2022Article
- The Rare, the Best: Spread of Antimalarial-Resistant Plasmodium falciparum Parasites byMicrobiology spectrum · 2021Article
- Higher gametocyte production and mosquito infectivity in chronic compared to incident Plasmodium falciparum infections.Nature communications · 2021Article
- Comparative analysis of Plasmodium falciparum dihydrofolate-reductase gene sequences from different regions of India.Heliyon · 2020Article
- Efficient Transmission of Mixed Plasmodium falciparum/vivax Infections From Humans to Mosquitoes.The Journal of infectious diseases · 2020Article
- Antimalarial Properties of Isoquinoline Derivative fromBioMed research international · 2020Article
- Mosquitoes as a feasible sentinel group for anti-malarial resistance surveillance by Next Generation Sequencing of Plasmodium falciparum.Malaria journal · 2019Article
- Atovaquone-Proguanil in Combination With Artesunate to Treat Multidrug-ResistantOpen forum infectious diseases · 2019Article
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10 authors at 1 institution in 1 country.
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Abstract
Surveillance for drug-resistant parasites in human blood is a major effort in malaria control. Here we report contrasting antifolate resistance polymorphisms in Plasmodium falciparum when parasites in human blood were compared with parasites in Anopheles vector mosquitoes from sleeping huts in rural Zambia. DNA encoding P. falciparum dihydrofolate reductase (EC 1.5.1.3) was amplified by PCR with allele-specific restriction enzyme digestions. Markedly prevalent pyrimethamine-resistant mutants were evident in human P. falciparum infections--S108N (>90%), with N51I, C59R, and 108N+51I+59R triple mutants (30-80%). This resistance level may be from selection pressure due to decades of sulfadoxine/pyrimethamine use in the region. In contrast, cycloguanil-resistant mutants were detected in very low frequency in parasites from human blood samples-S108T (13%), with A16V and 108T+16V double mutants (∼4%). Surprisingly, pyrimethamine-resistant mutants were of very low prevalence (2-12%) in the midguts of Anopheles arabiensis vector mosquitoes, but cycloguanil-resistant mutants were highly prevalent-S108T (90%), with A16V and the 108T+16V double mutant (49-57%). Structural analysis of the dihydrofolate reductase by in silico modeling revealed a key difference in the enzyme within the NADPH binding pocket, predicting the S108N enzyme to have reduced stability but the S108T enzyme to have increased stability. We conclude that P. falciparum can bear highly host-specific drug-resistant polymorphisms, most likely reflecting different selective pressures found in humans and mosquitoes. Thus, it may be useful to sample both human and mosquito vector infections to accurately ascertain the epidemiological status of drug-resistant alleles.
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