Understanding artemisinin-resistant malaria: what a difference a year makes

Abstract

Purpose of review: The emergence of artemisinin resistance in Southeast Asia (SEA), where artemisinin combination therapies (ACTs) are beginning to fail, threatens global endeavors to control and eliminate Plasmodium falciparum malaria. Future efforts to prevent the spread of this calamity to Africa will benefit from last year's tremendous progress in understanding artemisinin resistance.

Recent findings: Multiple international collaborations have established that artemisinin resistance is associated with slow parasite clearance in patients, increased survival of early-ring-stage parasites in vitro, single-nucleotide polymorphisms (SNPs) in the parasite's kelch protein gene (K13), parasite 'founder' populations sharing a genetic background of four additional SNPs, parasite transcriptional profiles reflecting an 'unfolded protein response' and decelerated parasite development, and elevated parasite phosphatidylinositol-3-kinase activity. In Western Cambodia, where the K13 C580Y mutation is approaching fixation, the frontline ACT is failing to cure nearly half of patients, likely due to partner drug resistance. In Africa, where dozens of K13 mutations have been detected at low frequency, there is no evidence yet of artemisinin resistance.

Summary: In SEA, clinical and epidemiological investigations are urgently needed to stop the further spread of artemisinin resistance, monitor the efficacy of ACTs where K13 mutations are prevalent, identify currently-available drug regimens that cure ACT failures, and rapidly advance new antimalarial compounds through preclinical studies and clinical trials.

Fig 1. Plasmodium falciparum kelch13 (K13) protein

The parasite K13 protein consists of Plasmodium-specific sequences, a BTB-POZ domain, and six kelch domains that are predicted to form a six-blade propeller. In the structural model, the original M476I mutation discovered by Ariey et al. [22] and six other mutations associated with artemisinin resistance in Southeast Asia are shown. Adapted from [22]. Molecular structure courtesy of Dr. Odile Puijalon, Institut Pasteur, Paris, France.

Fig 2. Two proposed mechanisms of artemisinin sensitivity and resistance in Plasmodium falciparum

A. In artemisinin-sensitive parasites, wild-type K13 (green) binds a putative transcription factor and targets it for degradation. In artemisinin-resistant parasites, on the other hand, mutant K13 (red) fails to bind this putative transcription factor, which is free to upregulate genes involved in the antioxidant response. In this “protected” state, parasites are better prepared to handle the oxidative stress imposed by activated artemisinins, for example, by refolding oxidatively-damaged proteins. B. In artemisinin-sensitive parasites, wild-type K13 binds PI3K and targets it for degradation. In artemisinin-resistant parasites, on the other hand, mutant K13 fails to bind PI3K, leading to increased PI3K and PI3P levels. In this “protected” state, high PI3P levels are presumably able to promote the survival of parasites exposed to artemisinins, for example, my mediating membrane fusion events involved in parasite growth. Adapted from [46].