The transcription factor BACH1 promotes tissue damage and host susceptibility in <i>Mycobacterium tuberculosis</i> infection by reducing expression of Gpx4, a major negative regulator of ferroptosis
Bibliographic record
Abstract
Abstract Ferroptosis is a type of regulated necrotic cell death induced by the acumulation of free iron and lipid peroxides. We have previously described a role for ferroptosis in Mtb-induced macrophage necrosis based on its biochemical requirements and its blockade both in vitro and in vivo by a lipid peroxidation inhibitor (fer-1). To help validate these findings and further delineate the mechanism involved we have analyzed Mtb-induced cellular necrosis and host resistance in mice deficient in or overexpressing glutathione peroxidase (Gpx4), an essential regulator of ferroptosis. To do so we generated conditional-knockout mice for Gpx4 by using creERT2, CD45cre and LysMcre systems targeting different cell compartments. After aerosol low dose Mtb infection these conditional-knockout mice showed both increased lung necrosis and elevated pulmonary and splenic bacterial burdens. In the opposite direction, Gpx4-overexpressing mice infected at high dose with Mtb were found to display decreased bacterial burdens as well as reduced pulmonary necrosis. Genetic deletion of BACH1, a transcription factor known to repress antioxidant genes including Gpx4, increased the levels of intracellular glutathione as well as enhanced expression of Gpx4 during Mtb infection in vitro and in vivo. Moreover, Bach1−/− mice infected at high dose with Mtb displayed a significant reduction in bacterial loads and lung necrosis along with lowered levels of lipid peroxides as well as enhanced survival. Together, these findings provide genetic evidence further delineating the role of ferroptosis as a mechanism of host cell death and tissue necrosis in Mtb infection and implicate both Gpx4 and Bach1 as potential targets for host-direct therapy of tuberculosis.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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 source (direct Gemma or distilled Codex), 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".