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Research article - Peer-reviewed, 2022

Plasmodium falciparum Drug Resistance Genes pfmdr1 and pfcrt In Vivo Co-Expression During Artemether-Lumefantrine Therapy

Silva, M.; Malmberg, M.; Otienoburu, S. D.; Bjorkman, A.; Ngasala, B.; Martensson, A.; Gil, J. P.; Veiga, M. I.


Background: Artemisinin-based combination therapies (ACTs) are the global mainstay treatment of uncomplicated Plasmodium falciparum infections. PfMDR1 and PfCRT are two transmembrane transporters, associated with sensitivity to several antimalarials, found in the parasite food vacuole. Herein, we explore if their relatedness extends to overlapping patterns of gene transcriptional activity before and during ACT administration.Methods: In a clinical trial performed in Tanzania, we explored the pfmdr1 and pfcrt transcription levels from 48 patients with uncomplicated P. falciparum malaria infections who underwent treatment with artemether-lumefantrine (AL). Samples analyzed were collected before treatment initiation and during the first 24 h of treatment. The frequency of PfMDR1 N86Y and PfCRT K76T was determined through PCR-RFLP or direct amplicon sequencing. Gene expression was analyzed by real-time quantitative PCR.Results: A wide range of pre-treatment expression levels was observed for both genes, approximately 10-fold for pfcrt and 50-fold for pfmdr1. In addition, a significant positive correlation demonstrates pfmdr1 and pfcrt co-expression. After AL treatment initiation, pfmdr1 and pfcrt maintained the positive co-expression correlation, with mild downregulation throughout the 24 h post-treatment. Additionally, a trend was observed for PfMDR1 N86 alleles and higher expression before treatment initiation.Conclusion: pfmdr1 and pfcrt showed significant co-expression patterns in vivo, which were generally maintained during ACT treatment. This observation points to relevant related roles in the normal parasite physiology, which seem essential to be maintained when the parasite is exposed to drug stress. In addition, keeping the simultaneous expression of both transporters might be advantageous for responding to the drug action.


malaria; mRNA; in vivo; P; falciparum; artemether-lumefantrine

Published in

Frontiers in Pharmacology
2022, volume: 13, article number: 868723

Authors' information

Silva, M.
Universidade do Minho
Swedish University of Agricultural Sciences, Department of Animal Breeding and Genetics
Otienoburu, S. D.
Johnson C Smith University
Bjorkman, A.
Karolinska Institutet
Ngasala, B.
Muhimbili University of Health and Allied Sciences
Martensson, A.
Uppsala University
Gil, J. P.
Karolinska Institutet
Gil, J. P.
Universidade Nova de Lisboa
Veiga, M. I.
Universidade do Minho

Sustainable Development Goals

SDG3 Good health and wellbeing

UKÄ Subject classification

Pharmacology and Toxicology

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