Ivermectin (IVM), a potent endectocide, has attracted significant interest as a potential component in combination drug therapies for malaria control. Its efficacy has been demonstrated in multiple clinical trials, where IVM paired with frontline drugs effectively controlled malaria in endemic regions across Africa. However, the precise mechanisms of IVM’s action against malaria parasites and the development of resistance to this drug remain unclear. This study investigates these mechanisms by assessing ultrastructural changes in P. falciparum induced by IVM and in adapted IVM-resistant mutants to elucidate resistance pathways.
In drug-sensitive parasites, IVM treatment arrested development and induced cell death predominantly at the trophozoite stage, the parasite’s most metabolically active phase. Scanning Electron Microscopy (SEM) showed that knob surface structures became enlarged and reduced in density, suggesting that IVM disrupts cellular transport processes. Transmission Electron Microscopy (TEM) further revealed that IVM affects mitochondrial function and trafficking across the parasitophorous vacuole membrane (PVM), resulting in PV dilation and consequent deformation of knob structures.
In contrast, adapted IVM-resistant (IVMR) parasites displayed an ability to survive and replicate under continuous IVM pressure. Scanning Transmission Electron Microscopy (STEM) indicated that these resistant parasites counteract IVM’s effects by resolving PVM dilation. However, resistance also led to altered protein trafficking patterns, with segregated digestive vacuoles (DVs) and enlarged mitochondria, likely reflecting rewired transport pathways. Morphological observations were supported by transcriptomic analysis, which showed downregulation in the exportome of IVM-resistant parasites relative to wild-type, with reduced expression of surface proteins (pfEMP1, Rifin, PHIST, Stevor, and Clag family). Additionally, transcriptomic data revealed rewired internal protein trafficking in resistant parasites, evidenced by altered expression of genes involved in prenylation (Rabs) and vesicle mediation (COPI).
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