Affiliation:
1. Centre de Recherche Médicale et Sanitaire
2. University of Notre Dame
3. University of Zinder-Niger
4. University Abdou Moumouni of Niamey-Niger
5. Centre National de Référence du Paludisme à Paris en France
6. University of Georgia
Abstract
Abstract
Background: Artemisinin-based combination therapy (ACT) is the most effective treatment for malaria, and has significantly reduced morbimortality. Polymorphisms associated with the Plasmodium falciparum kelch gene (Pfkelch13) propeller domains have been associated with delayed parasite clearance even with ACT treatment.
Methods: The Pfkelch13gene was sequenced from P. falciparum infected patients (n=159) with uncomplicated malaria in Niger.An adequate clinical and parasitological response (ACPR) was reported in 155 patients. Four (n=4) patients had treatment failure (TF) that were not reinfections - two of which had late parasitological failures (LPF) and two had late clinical failures (LCF).
Results: Thirteen single nucleotide polymorphisms (SNPs) were identified of which eight were non synonymous (NSY) (C469R, T508S, S515T, A578S, I465V, I437V, E506L, N197D), and five were synonymous (SY) (H298H, H385H, P443P, P715P, L514L).
Six SNP (C469R, H298H, E506L, N197D, H385H, P715P) were present before ACT treatment, while seven mutations (C469R, T508S, S515T, L514L, P443P, I437V, I465V) were selected by Artemether lumefantrine (AL) - five of which were non synonymous (C469R, T508S, S515T, I437V, I465V). Artesunate amodiaquine (ASAQ) has selected any mutation.
One sample presented three cumulatively non-synonymous SNPs - C469R, T508S, S515T.
This study demonstrates intra host selection of Pfkelch13 gene NS by AL.
Conclusions: The study highlights the importance of LCF and LPF parasites in the selection of resistance to ACT. Further studies using gene editing are required to confirm the potential implication of resistance to ACT with the most common S515T and T508S mutations. It would also be important to elucidate the role of cumulative mutations.
GenBank accession numbers: MZ364160, MZ364-213
Publisher
Research Square Platform LLC
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