Unraveling the Mechanisms of ACT Resistance in Africa: Genetic and Phenotypic Insights

Artemisinin - based combination therapies (ACTs) are critical for malaria control worldwide. Therefore, monitoring antimalarial drug resistance is vital, usually based on molecular surveillance of resistance markers. To date, ACT resistance is spread in Asia but still constrained in Africa, where emergence and spread dynamics are different. Artemether - lumefantrine is the most common ACT in East Africa, sporadic cases of treatment failure associated with lumefantrine (LF) and artemisinin (ART) resistance have been reported in Rwanda. ART resistance is associated with specific mutations in pfk13, among which 561H validated marker has been described in Rwanda at an average frequency of 19% in 2023. Although this marker has been associated with a delay in parasite clearance, phenotypic differences were observed between strains containing this marker. These findings suggest that the ACT resistance mechanism involves different mediators, being influenced by genetic background. This project aims to characterize this complexity through a multifactorial genomic and transcriptomic profiling of Rwandan samples combined with phenotypic characterisation including drug susceptibility assays and fitness cost assays, to investigate transmission and multiplication cost. Then, identified potential resistance genetic mediators will be confirmed by gene – editing using CRISPR-Cas9 technology. The project will therefore improve surveillance and assessment of antimalarial resistance in Africa.