Effects of M. tuberculosis and HIV-1 infection on in vitro blood-brain barrier function
Bibliographic record
Abstract
BACKGROUND: Tuberculous meningitis is the most severe form of tuberculosis and HIV-1 co-infection worsens the already poor prognosis. However, how Mycobacterium tuberculosis crosses the blood-brain barrier and how HIV-1 influences tuberculous meningitis pathogenesis remains unclear. METHODS: Using human pericytes, astrocytes, endothelial cells, and microglia alone and combined in an in vitro blood-brain barrier model, we investigated the effect of Mycobacterium tuberculosis +/- HIV-1 co-infection on central nervous system cell entry and function. Cells and the blood-brain barrier model were infected with Mycobacterium tuberculosis and/or HIV-1 and we evaluated the effects of both infection on (i) cells susceptibility to Mycobacterium tuberculosis and its growth in cells by flow cytometry; (ii) modulation of blood-brain barrier permeability and Mycobacterium tuberculosis passage through it; (iii) viral and bacterial cytopathogenicity using the xCELLigence system; (iv) cell metabolic activity and ROS release using colorimetric assays; (v) extracellular glutamate concentration by fluorometric assay; (vi) the inflammatory response by Luminex; and (vii) endoplasmic reticulum stress by quantitative PCR. RESULTS: We demonstrated that Mycobacterium tuberculosis infects and multiplies in all cell types with HIV-1 increasing entry to astrocytes and pericytes, and growth in HIV-1 positive pericytes and endothelial cells. Mycobacterium tuberculosis also induces an increase of the blood-brain barrier permeability resulting in translocation of bacilli across it. Cytopathic effects include (i) increased markers of cellular stress (mitochondrial metabolic activity, unfolded protein response); (ii) ROS release; (iii) the induction of neurotoxic astrocytes; (iv) and the secretion of the excitotoxic neurotransmitter glutamate. Lastly, we observed distinct cell-type specific production of inflammatory and effector mediators. CONCLUSION: These results indicate that Mycobacterium tuberculosis can translocate the blood-brain barrier directly to initiate meningitis.
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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".