Adenosine Triphosphate Depletion of Erythrocytes Simulates the Phenotype Associated with Pyruvate Kinase Deficiency and Confers Protection against<i>Plasmodium falciparum</i>In Vitro
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Bibliographic record
Abstract
BACKGROUND: Erythrocytes from individuals with pyruvate kinase deficiency (PKD) are resistant to invasion by Plasmodium falciparum parasites, and erythrocytes infected with ring-stage parasites are preferentially cleared by macrophages in vitro. However, the underlying molecular basis of protection is unknown. In the present study, we examined adenosine triphosphate (ATP) levels in PKD erythrocytes (ie, erythrocytes from individuals with PKD) and determined whether depletion of ATP in normal erythrocytes would recapitulate the phenotype observed with PKD. METHODS: We examined ATP levels in homozygous PKLR(-/-) and heterozygous PKLR(+/-) human erythrocytes and used sodium fluoride treatment to inhibit ATP generation in normal human erythrocytes. RESULTS: We demonstrated that ATP levels are reduced in PKLR(-/-) (percentage of control erythrocytes, 26%; interquartile range [IQR], 21%-48%) and PKLR(+/-) erythrocytes (percentage of control erythrocytes, 64%; IQR, 60%-73%) and that there is a correlation between ATP levels in erythrocytes and both inhibition of parasite invasion and enhancement of phagocytosis of erythrocytes infected with ring-stage parasites. Analysis of ATP distribution in parasitized erythrocytes demonstrated that parasites invading PKD erythrocytes respond to low intraerythrocytic ATP levels by means of a parallel increase in parasite-derived ATP via up-regulation of P. falciparum-specific pyruvate kinase. CONCLUSION: These data suggest that reduced erythrocyte ATP levels may contribute to the protection displayed by PKD erythrocytes in vitro and may provide a model system with which to define the molecular basis of protection in inherited PKD.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 it