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Background <p>Tuberculous meningitis is the most severe form of tuberculosis and HIV-1 co-infection worsens the already poor prognosis. However, how <i>Mycobacterium tuberculosis</i> crosses the blood-brain barrier and how HIV-1 influences tuberculous meningitis pathogenesis remains unclear.</p> Methods <p>Using human pericytes, astrocytes, endothelial cells, and microglia alone and combined in an in vitro blood-brain barrier model, we investigated the effect of <i>Mycobacterium tuberculosis</i> +/- HIV-1 co-infection on central nervous system cell entry and function. Cells and the blood-brain barrier model were infected with <i>Mycobacterium tuberculosis</i> and/or HIV-1 and we evaluated the effects of both infection on (i) cells susceptibility to <i>Mycobacterium tuberculosis</i> and its growth in cells by flow cytometry; (ii) modulation of blood-brain barrier permeability and <i>Mycobacterium tuberculosis</i> 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.</p> Results <p>We demonstrated that <i>Mycobacterium tuberculosis</i> 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. <i>Mycobacterium</i><i> tuberculosis</i> 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.</p> Conclusion <p>These results indicate that <i>Mycobacterium tuberculosis</i> can translocate the blood-brain barrier directly to initiate meningitis.</p>

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Effects of M. tuberculosis and HIV-1 infection on in vitro blood-brain barrier function

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月26日

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  • Alizé Proust,
  • Katalin A. Wilkinson,
  • Robert J. Wilkinson

摘要

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.