Malaria parasite phenotypic heterogeneity and the power of single-cell technologies.

The two-host life cycle of the malaria parasite, combined with its ability to regulate gene expression and protein translation within a single clonal genotype, results in a remarkable potential for phenotypic heterogeneity. This heterogeneity presents underappreciated challenges to antimalarial interventions such as vaccines, drugs, and diagnostic tools, with parasites able to evolve resistance rapidly. Here we summarise current knowledge of the different mechanisms driving parasite phenotypic heterogeneity both at the gene and protein level. Centred on the most virulent human malaria parasite, Plasmodium falciparum, we explore the consequences of this diversity for antimalarial interventions and how single-cell technologies present an opportunity to study inter- and intra-clonal heterogeneity to better design future-proofed intervention strategies against this ancient disease.