The functions of K13 in P. falciparum are unknown, but this protein belongs to the kelch superfamily of proteins, which are characterized by the presence of a propeller-like domain that is involved in multiple protein–protein interactions. To confirm that the K13-propeller mutations are responsible for ART resistance, Straimer et al. used zinc-finger nucleases to engineer K13 in both P. falciparum clinical isolates (ART-resistant and ART-sensitive strains) and several drug-sensitive reference strains. The authors found that removing the K13-propeller mutations from several ART-resistant clinical isolates fully restored drug sensitivity, whereas insertion of these mutations into drug-sensitive parasites resulted in ART resistance. Interestingly, introduction of the C580Y mutation, which is the most common K13 mutation found in clinical isolates, resulted in increased levels of ART resistance in drug-sensitive P. falciparum clinical isolates compared with reference strains, suggesting that additional factors contribute to ART resistance in parasites isolated from endemic areas.
To understand how the K13-propeller mutations cause ART resistance, Mok et al. examined the transcriptomes of 1,043 P. falciparum isolates from patients with acute malaria, including drug-resistant and drug-sensitive strains. This analysis revealed that two classes of genes were differentially expressed in parasites carrying the K13-propeller mutations: genes associated with protein folding and repair — especially those involved in the unfolded protein response (UPR) — were upregulated in the drug-resistant isolates, whereas genes involved in DNA replication were downregulated in these parasites. Interestingly, the downregulation of genes involved in DNA replication was associated with an altered progression of P. falciparum through different developmental stages within erythrocytes; parasites with the K13-propeller mutations were arrested at the immature ring stage, rather than progressing to more mature stages such as trophozoites and early schizonts.
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