Cuproptosis-driven astrocyte reactivity exacerbates experimental cerebral malaria pathogenesis
Bibliographic record
Abstract
Abstract Background Cerebral malaria (CM), a lethal neurological complication of Plasmodium falciparum , is characterized by blood–brain barrier (BBB) disruption. Although astrocytes constitute essential components of the BBB neurovascular unit, their immunoregulatory functions during CM pathogenesis remain elusive. Clinical evidence of altered copper homeostasis in patients with CM, coupled with known associations between copper dysregulation and astrocyte reactivity, prompted investigation of cuproptosis—a copper-dependent programmed cell death pathway—in the disease progression of CM. Methods Using a P. berghei ANKA ( Pb A)-induced experimental CM (ECM) model in C57BL/6 mice, we evaluated pharmacological modulation with copper ionophore disulfiram (DSF) versus copper chelator tetrathiomolybdate (TTM). Parallel in vitro experiments assessed astrocytes stimulated by Pb A-infected red blood cells (iRBCs)/blood-stage soluble antigen ( Pb Ag) under DSF-CuCl 2 or TTM-CuCl 2 treatment. Results ECM mice demonstrated significant cerebral copper accumulation with concomitant upregulation of cuproptosis markers (SLC31A1, FDX1, DLAT, and DLST) and downregulation of ATP7A copper transporter. DSF administration exacerbated ECM progression through amplified parasitemia, aggravated BBB permeability, cerebral edema, and neuroinflammatory responses, whereas TTM treatment counteracted these pathological manifestations. Immunohistochemical analysis revealed DSF-induced astrocyte reactivity (GFAP + /Serping1 + ) with colocalization of cuproptosis markers (GFAP + -SLC31A1 + /FDX1 + /DLAT + /DLST + ), contrasting with TTM-mediated suppression. In vitro, DSF-CuCl 2 treatment augmented iRBC-stimulated astrocyte expression of reactivity markers (GFAP and Serping1), cuproptosis regulators (SLC31A1, FDX1, DLAT, and DLST), and proinflammatory mediators (CXCL10, tumor necrosis factor (TNF)-ɑ, interleukin (IL)-1β, and IL-6), but conversely reduced Pb Ag-stimulated cell viability. These effects were reversed by TTM-CuCl 2 treatment. Conclusions These findings establish that cuproptosis exacerbates ECM pathogenesis by promoting astrocyte reactivity, highlighting copper homeostasis modulation as a potential therapeutic strategy for CM. Graphical Abstract
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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 | 0.000 | 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 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".