Plasmodium falciparum kelch13 polymorphisms identified after treatment failure with artemisinin-based combination therapy in Niger

Malaria Journal

Research

Houzé Sandrine¹  Véronique Sarrasin-Hubert¹  Aboubacar Mahamadou²  Ibrahima Issa Arzika²  Ibrahim Maman Laminou²  Mahaman Moustapha Lamine³  Ilagouma Amadou Tidjani⁴  Eric Adehossi⁴  Ousman Mahmud⁵  Demba Sarr⁵  Neil F. Lobo⁶ 

[1] Centre National de Référence du Paludisme, Paris, France;Centre de Recherche Médicale et Sanitaire de Niamey, Niamey, Niger;Centre de Recherche Médicale et Sanitaire de Niamey, Niamey, Niger;Université André Salifou de Zinder, Zinder, Niger;University Abdou Moumouni of Niamey, Niamey, Niger;University of Georgia, Athens, USA;University of Notre Dame, Notre Dame, USA;

关键词: P. falciparum;    Resistance;    Artemisinin;    Pfkelch;    Niger;   

DOI  :  10.1186/s12936-023-04571-w

 received in 2022-12-18, accepted in 2023-04-24,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundArtemisinin-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) have been associated with delayed parasite clearance even with ACT treatment.MethodsThe Pfkelch13 gene 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).ResultsThirteen single nucleotide polymorphisms (SNPs) were identified of which seven were non-synonymous (C469R, T508S, R515T, A578S, I465V, I437V, F506L,), and three were synonymous (P443P, P715P, L514L). Three SNP (C469R, F506L, P715P) were present before ACT treatment, while seven mutations (C469R, T508S, R515T, L514L, P443P, I437V, I465V) were selected by artemether/lumefantrine (AL)—five of which were non-synonymous (C469R, T508S, R515T, I437V, I465V). Artesunate/amodiaquine (ASAQ) has selected any mutation. One sample presented three cumulatively non-synonymous SNPs—C469R, T508S, R515T.ConclusionsThis study demonstrates intra-host selection of Pfkelch13 gene by AL. 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 R515T and T508S mutations. It would also be important to elucidate the role of cumulative mutations.

【 授权许可】

CC BY   
© The Author(s) 2023

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