Functional analysis of Plasmodium falciparum subpopulations associated with artemisinin resistance in Cambodia

Background: Plasmodium falciparum malaria is one of the most widespread parasitic infections in humans and remains a leading global health concern. Malaria elimination efforts are threatened by the emergence and spread of resistance to artemisinin-based combination therapy, the first-line treatment of malaria. Promising molecular markers and pathways associated with artemisinin drug resistance have been identified, but the underlying molecular mechanisms of resistance remains unknown. The genomic data from early period of emergence of artemisinin resistance (2008–2011) was evaluated, with aim to define k13 associated genetic background in Cambodia, the country identified as epicentre of anti-malarial drug resistance, through characterization of 167 parasite isolates using a panel of 21,257 SNPs. Results: Eight subpopulations were identified suggesting a process of acquisition of artemisinin resistance consistent with an emergence-selection-diffusion model, supported by the shifting balance theory. Identification of population specific mutations facilitated the characterization of a core set of 57 background genes associated with artemisinin resistance and associated pathways. The analysis indicates that the background of artemisinin resistance was not acquired after drug pressure, rather is the result of fixation followed by selection on the daughter subpopulations derived from the ancestral population. Conclusions: Functional analysis of artemisinin resistance subpopulations illustrates the strong interplay between ubiquitination and cell division or differentiation in artemisinin resistant parasites. The relationship of these pathways with the P. falciparum resistant subpopulation and presence of drug resistance markers in addition to k13, highlights the major role of admixed parasite population in the diffusion of artemisinin resistant background. The diffusion of resistant genes in the Cambodian admixed population after selection resulted from mating of gametocytes of sensitive and resistant parasite populations. (Résumé d'auteur

MOESM11 of Functional analysis of Plasmodium falciparum subpopulations associated with artemisinin resistance in Cambodia

Additional file 11. Network representation of overlapping gene sets associated with ART-R subpopulations (set of 265 genes) and the ART-S subpopulation KH1.2 common resistance background (set of 168 genes). The networks for the two gene sets based on co-expression data are recovered from STRING v10. The edges connecting the genes, have the co-expression evidence score greater than 0.5. The nodes and edges in “red” color represent the interaction network based on coexpression for ART-R subpopulations gene set. The nodes and edges in “white” color represent the interaction network based on coexpression for ART-S sunpopulation KH1.2 common resistance background genes set. For the ART-R subpopulation specific genes set, out of the 265 genes only 173 genes are used for overlap and for the KH1.2 common resistance background genes set, out of 168 only 113 genes are used for overlap. Other genes (nodes) are removed either because of no interactions (before/after overlap) or STRING confidence score below 0.5. The representation of overlapping coexpression network is done in Cytoscape v3.2.1 using the DyNet Analyzer plugin