Abstract
Chloroquine (CQ) treatment failure in Plasmodium falciparum parasites has been documented for decades, but the pharmacological explanation of this phenotype is not fully understood. Current concepts attribute CQ resistance to reduced accumulation of the drug at a given external CQ concentration ([CQ]ex) in resistant compared to sensitive parasites. The implication of this explanation is that the mechanisms of CQ-induced toxicity in resistant and sensitive strains are similar once lethal internal concentrations have been reached. To test this hypothesis, we investigated the mechanism of CQ-induced toxicity in CQ-sensitive (CQS) versus CQ-resistant (CQR) parasites by analyzing the time-course of cellular responses in these strains after exposure to varying [CQ]ex as determined in 72 h toxicity assays. Parasite killing was delayed in CQR parasites for up to 10 h compared to CQS parasites when exposed to equipotent [CQ]ex. In striking contrast, brief exposure (1 h) to lethal [CQ]ex in CQS but not CQR parasites caused the appearance of hitherto undescribed hemozoin (Hz)-containing compartments in the parasite cytosol. Hz-containing compartments were very rarely observed in CQR parasites even after CQ exposures sufficient to cause irreversible cell death. These findings challenge current concepts that CQ killing of malaria parasites is solely concentration-dependent, and instead suggest that CQS and CQR strains fundamentally differ in the consequences of CQ exposure.
Highlights
Extensive malaria control measures have significantly decreased the incidence of malaria worldwide[1], antimalarial drug resistance remains a serious concern
Resistance to CQ, as indicated by IC50 values, was partially reversed in CQR strains by co-incubation with 1 μM verapamil (VP), while no significant difference in IC50 values was observed with VP in CQS parasite strains (p > 0.05), as expected
We show (i) the appearance of dark cytosolic structures (DCS) containing Hz in the cytosol of CQS but not CQR parasites treated with CQ, (ii) the elimination of DCS in CQS parasites treated with CQ in the presence of VP, and (iii) the delayed onset of irreversibly lethal damage in CQR versus CQS parasites exposed to equitoxic [CQ]ex
Summary
Extensive malaria control measures have significantly decreased the incidence of malaria worldwide[1], antimalarial drug resistance remains a serious concern. Chloroquine (CQ), a 4-aminoquinoline derivative, has been a highly efficacious, safe and low-cost antimalarial drug Resistance to this drug spread worldwide and required decades to evolve[2], but has dramatically limited its efficacy against Plasmodium falciparum, the most lethal species of human malaria parasites. CQR parasites are reported to tolerate higher CQ levels in the DV than CQS strains, an observation that cannot be explained by simple concentration-dependent toxicity effects of CQ. Our findings show that CQS and CQR parasites display distinct cellular responses as a consequence of CQ exposure These results suggest that our understanding of the mechanism of action of CQ requires refinement, and that cell biological effects of CQ on sensitive and resistant parasites need to be investigated in parallel
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