XB-ART-52262
PLoS Pathog
2016 Jul 21;127:e1005725. doi: 10.1371/journal.ppat.1005725.
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Molecular Mechanisms for Drug Hypersensitivity Induced by the Malaria Parasite's Chloroquine Resistance Transporter.
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Mutations in the Plasmodium falciparum 'chloroquine resistance transporter' (PfCRT) confer resistance to chloroquine (CQ) and related antimalarials by enabling the protein to transport these drugs away from their targets within the parasite's digestive vacuole (DV). However, CQ resistance-conferring isoforms of PfCRT (PfCRTCQR) also render the parasite hypersensitive to a subset of structurally-diverse pharmacons. Moreover, mutations in PfCRTCQR that suppress the parasite's hypersensitivity to these molecules simultaneously reinstate its sensitivity to CQ and related drugs. We sought to understand these phenomena by characterizing the functions of PfCRTCQR isoforms that cause the parasite to become hypersensitive to the antimalarial quinine or the antiviral amantadine. We achieved this by measuring the abilities of these proteins to transport CQ, quinine, and amantadine when expressed in Xenopus oocytes and complemented this work with assays that detect the drug transport activity of PfCRT in its native environment within the parasite. Here we describe two mechanistic explanations for PfCRT-induced drug hypersensitivity. First, we show that quinine, which normally accumulates inside the DV and therewithin exerts its antimalarial effect, binds extremely tightly to the substrate-binding site of certain isoforms of PfCRTCQR. By doing so it likely blocks the normal physiological function of the protein, which is essential for the parasite's survival, and the drug thereby gains an additional killing effect. In the second scenario, we show that although amantadine also sequesters within the DV, the parasite's hypersensitivity to this drug arises from the PfCRTCQR-mediated transport of amantadine from the DV into the cytosol, where it can better access its antimalarial target. In both cases, the mutations that suppress hypersensitivity also abrogate the ability of PfCRTCQR to transport CQ, thus explaining why rescue from hypersensitivity restores the parasite's sensitivity to this antimalarial. These insights provide a foundation for understanding clinically-relevant observations of inverse drug susceptibilities in the malaria parasite.
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Species referenced: Xenopus laevis
Genes referenced: app
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Fig 1. Isoforms of PfCRTK1 localize to the surface of Xenopus oocytes.(A) Immunofluorescence microscopy was used to localize PfCRT in the oocyte. In each case, the expression of the PfCRT variant resulted in a fluorescent band external to the pigment layer, indicating that the protein was expressed in the oocyte plasma membrane. The band was not present in noninjected oocytes. The images are representative of at least two independent experiments (performed using oocytes from different frogs), within which images were obtained from a minimum of three oocytes per oocyte type. (B) The level of PfCRT protein in the oocyte membrane was semiquantified using a western blot method [42]. The analysis included PfCRTK1 as a positive control, to which the other band intensity values were normalized. The data are the mean + SEM of at least five independent experiments (performed using oocytes from different frogs), within which measurements were averaged from two independent replicates. There were no significant differences in expression levels between constructs (P > 0.05; one-way ANOVA); hence, all of the PfCRT variants were present at similar levels in the oocyte membrane. |
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Fig 2. CQ, quinine, and quinidine transport activities differ significantly between isoforms of PfCRTK1.Noninjected oocytes accumulate low levels of CQ, quinine, and quinidine via simple diffusion of the neutral species of the drug [29, 30]. This represents the background level of drug accumulation. In all cases, the concentration of the [3H]drug under study was 0.25 μM. (A) The uptake of [3H]CQ was measured at pH 6.0 and in the presence of 15 μM unlabeled CQ. The rates of CQ uptake (pmol per oocyte/h) in noninjected oocytes and oocytes expressing PfCRTK1 were 0.98 ± 0.13 and 6.75 ± 0.94, respectively. (B, C) The uptake of [3H]quinine or [3H]quinidine was measured at pH 5.0 and in the presence of 1 μM of the respective unlabeled drug. The rates of uptake (pmol per oocyte/h) in noninjected oocytes and oocytes expressing PfCRTK1 were 0.10 ± 0.01 and 0.55 ± 0.03, respectively, for quinine and 0.063 ± 0.010 and 0.38 ± 0.08, respectively, for quinidine. Note that the relatively low total concentration of quinine and quinidine (1.25 μM) used in these assays enabled the detection of [3H]quinine transport via the 76I-PfCRTK1 isoform. However, this low drug concentration also resulted in rates of quinine and quinidine transport that were 10â15 times lower than those measured for CQ (a difference which corresponds well with the ~12-fold reduction in the total concentration of quinine or quinidine relative to the total concentration of CQ). In all panels, drug uptake is expressed relative to that measured in oocytes expressing PfCRTK1 and the data are the mean + SEM of at least five independent experiments (performed using oocytes from different frogs), within which measurements were made from 10 oocytes per treatment. The asterisks denote a significant difference in drug uptake between the noninjected treatment and that measured in oocytes expressing a variant of PfCRT: *P < 0.05; **P < 0.01; ***P < 0.001 (one-way ANOVA). |
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Fig 3. Isoforms of PfCRTK1 from amantadine-hypersensitive parasites transport amantadine.(A) Amantadine inhibits the transport of [3H]CQ via 76I-PfCRTK1 and 76I,369F-PfCRTK1 in a concentration-dependent manner (IC50s of 186 ± 16 and 174 ± 26 μM, respectively). (B) The uptake of [3H]amantadine (0.146 μM) in the absence and presence of verapamil or saquinavir. The measurements were undertaken at pH 5.0 and in the presence of 50 μM unlabeled amantadine. (C) The PfCRT-mediated transport of [3H]amantadine. Using the data shown for the solvent control in panel B, the component of [3H]amantadine transport attributable to PfCRT was calculated by subtracting the background level of accumulation (i.e., the average of the uptake measured in noninjected oocytes and oocytes expressing 76K-PfCRTK1) from that measured for each of the oocyte types. The rates of amantadine uptake (nmol per oocyte/h) in noninjected oocytes and PfCRTK1-expressing oocytes were 5.4 ± 0.9 and 12 ± 2.8, respectively. The asterisks denote a significant difference from the noninjected control: *P < 0.05; **P < 0.01; ***P < 0.001 (one-way ANOVA). (D) Trans-stimulation of PfCRT-mediated [3H]CQ transport by unlabeled amantadine. The oocytes were microinjected with a buffer control or with buffer containing amantadine, spermine, or histidine. The estimated intracellular concentrations ([compound]i) are indicated. The asterisks denote a significant difference from the relevant buffer-injected control. (E) Concentration-dependence of the trans-stimulation of [3H]CQ uptake by amantadine. The oocytes were microinjected with buffer containing amantadine to achieve an estimated [amantadine]i of 1 to 20 mM. The app Km and app Vmax values are the apparent kinetic parameters for the trans-stimulatory effect of amantadine. The data show CQ uptake above that measured in the relevant buffer-injected control; the total rates of CQ uptake are presented in S6 Fig. The noninjected data overlays the data obtained with oocytes expressing PfNT1, PfCRT3D7, or 76K-PfCRTK1. (F) A magnified plot of the 76I-PfCRTK1 and 76I,369F-PfCRTK1 data from panel E. In all panels, the data are the mean ± SEM of five independent experiments (performed using oocytes from different frogs), within which measurements were made from 10 oocytes per treatment. Where not shown, error bars fall within the symbols. |
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Fig 4. Amantadine is a substrate of PfCRTDd2 and PfCRT7G8, and not of wild-type PfCRT, in situ.The rate of concanamycin A-induced DV alkalinization (expressed as the inverse of the half-time for DV alkalinization) in the C2GC03 (CQ-sensitive, expressing PfCRT3D7), C4Dd2 (CQ-resistant, expressing PfCRTDd2), and C67G8 (CQ-resistant, expressing PfCRT7G8) transfectant lines was measured in the absence and presence of amantadine (AMT), CQ, or verapamil (VP). The effect of amantadine on the DV alkalinization rate was also measured in the presence of verapamil (final concentration of 50 μM). The drugs were added to suspensions of saponin-isolated trophozoite-stage parasites containing fluorescein-dextran in their DVs 4 min before the addition of concanamycin A (100 nM). CQ was added at a concentration of 2.5 μM and the concentration of amantadine was 10 μM. Consistent with previous studies, the addition of CQ elevated the rate of alkalinization in both of the CQ-resistant lines and had a small buffering effect in the C2GC03 parasites [34â36, 46]. The biological basis for the difference in the rate of CQ-dependent alkalinization between the two CQ-resistant lines is currently unclear, but could be due to differences in (1) the expression of PfCRT, (2) the transport properties of the two PfCRT isoforms, (3) the volume of the DV, and/or (4) the concentration of PfCRTâs natural substrates within the DV. The data are the mean + SEM of five independent experiments (performed on different days). The asterisks denote a significant difference from the relevant solvent control: ***P < 0.001 (one-way ANOVA). |
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Fig 5. Molecular mechanisms for the drug hypersensitivities induced by PfCRT isoforms in the malaria parasite.(A) The variants of PfCRTK1 that contain 72R, 76K, 163R, 352K, or 352R (R/K) do not possess significant quinine (QN) transport activity. The drug would therefore remain in the parasiteâs DV where it exerts an anti-hemozoin effect that kills the parasite, which is consistent with the QN-sensitive (S) status of the respective lines. PfCRTK1 (76T) is able to transport QN out of the DV and thereby imparts low-level resistance (low-R) to QN. By contrast, 76I-PfCRTK1 has an extremely high affinity for QN coupled with an extremely low maximum rate of transport. This causes QN to clog the binding site of 76I-PfCRTK1, thereby blocking the transport of the natural substrate. Hence, the QN-hypersensitivity (hyper-S) observed in 106/176I parasites results from QN exerting two killing effectsâanti-hemozoin and anti-PfCRTCQR. The gain of a positively-charged residue at position 72 or 352 (76I R/K) prevents the interaction of the transporter with QN and returns the parasites to QN-sensitive status. (B) Amantadine (AMT) is a relatively poor inhibitor of both 76I-PfCRTK1 and 76I,369F-PfCRTK1, making it unlikely that the AMT-hypersensitivity of CQ-resistant parasites is due to an anti-PfCRTCQR effect. The isoforms of PfCRT from AMT-hypersensitive parasites (PfCRTK1 and 76I-PfCRTK1) have the ability to transport this weak-base drug out of the DV (where it accumulates) whereas those from AMT-sensitive parasites either do not possess significant AMT transport activity (e.g., 76K-PfCRTK1 and 163R,356V-PfCRTK1; R/K) or transport AMT with low affinity and low capacity (76I,369F-PfCRTK1). The data therefore converge on a scenario in which AMT exerts its main antimalarial activity in the cytosol and AMT-hypersensitivity arises from the redistribution of the drug from the DV into the cytosol via a PfCRTCQR variant (e.g., PfCRTK1 or 76I-PfCRTK1). |
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