Uptake of a fluorescently tagged chloroquine analogue is reduced in CQ-resistant compared to CQ-sensitive Plasmodium falciparum parasites
Bibliographic record
Abstract
Abstract Background Chloroquine (CQ) was the drug of choice for decades in the treatment of falciparum malaria until resistance emerged. CQ is suggested to accumulate in the parasite’s digestive vacuole (DV), where it unfolds its anti-malarial properties. Discrepancies of CQ accumulation in CQ-sensitive (CQS) and CQ-resistant (CQR) strains are thought to play a significant role in drug susceptibility. Analysis of CQ transport and intracellular localization using a fluorescently tagged CQ analogue could provide much needed information to distinguish susceptible from resistant parasite strains. The fluorescently tagged CQ analogue LynxTag-CQ™ GREEN (CQ GREEN ) is commercially available and was assessed for its suitability. Methods IC 50 values were determined for both CQ and CQ GREEN in two CQS and two CQR Plasmodium falciparum strains. Buffer solutions with varying pH were used to determine pH-dependent localization of CQ GREEN in infected red blood cells. Before CQS or CQR parasites were exposed to different pH buffers, they were pre-loaded with varying concentrations of CQ GREEN for up to 7 h. Intracellular accumulation was analysed using live cell confocal microscopy. CQ GREEN uptake rates were determined for the cytosol and DV in the presence and absence of verapamil. Results In CQS strains, twofold higher IC 50 values were determined for the CQ GREEN analogue compared to CQ. No significant differences in IC 50 values were observed in CQR strains. Addition of verapamil reversed drug resistance of CQR strains to both CQ and CQ GREEN . Live cell imaging revealed that CQ GREEN fluorescence was mainly seen in the cytosol of most parasites, independent of the concentration used. Incubation periods of up to 7 h did not influence intracellular localization of CQ GREEN . Nevertheless, CQ GREEN uptake rates in CQR strains were reduced by 50% compared to CQS strains. Conclusion Although fluorescence of CQ GREEN was mainly seen in the cytosol of parasites, IC 50 assays showed comparable efficacy of CQ GREEN and CQ in parasite killing of CQS and CQR strains. Reduced uptake rates of CQ GREEN in CQR strains compared to CQS strains indicate parasite-specific responses to CQ GREEN exposure. The data contains valuable information when CQ GREEN is used as an analogue for CQ.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".