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Updated: Aug 6, 2026
A Rat Model of EcoHIV Brain Infection
Published on: January 21, 2021
Effects of M. tuberculosis and HIV-1 infection on in vitro blood-brain barrier function
Alizé Proust1, Katalin A Wilkinson2,3, Robert J Wilkinson2,3,4
1The Francis Crick Institute, Midland Road, London, NW1 1AT, UK. alize.proust@crick.ac.uk.
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.
Insights
Tuberculosis bacteria can cross the blood-brain barrier directly, causing meningitis. HIV-1 co-infection worsens this process by increasing bacterial entry and growth in brain cells.
Area of Science:
- Neuroscience
- Infectious Diseases
- Immunology
Background:
- Tuberculous meningitis (TBM) is a severe form of tuberculosis with a poor prognosis, especially with HIV-1 co-infection.
- The mechanisms of Mycobacterium tuberculosis (Mtb) crossing the blood-brain barrier (BBB) and HIV-1's role in TBM pathogenesis are not fully understood.
Purpose of the Study:
- To investigate how Mtb interacts with the human BBB in the presence and absence of HIV-1.
- To elucidate the cellular and molecular mechanisms underlying Mtb translocation across the BBB and its impact on central nervous system (CNS) cells.
Main Methods:
- An in vitro human BBB model using pericytes, astrocytes, endothelial cells, and microglia was employed.
- Cells and BBB models were infected with Mtb +/- HIV-1 to assess bacterial entry, growth, BBB permeability, cytopathogenicity, cellular stress, glutamate release, inflammation, and endoplasmic reticulum stress.
Main Results:
- Mtb infects and multiplies in all CNS cell types, with HIV-1 enhancing Mtb entry into astrocytes and pericytes, and growth in pericytes and endothelial cells.
- Mtb increases BBB permeability, allowing bacterial translocation, and induces cellular stress, ROS release, neurotoxic astrocytes, and glutamate secretion.
- Distinct cell-type specific inflammatory responses were observed.
Conclusions:
- Mtb can directly translocate the BBB to initiate meningitis.
- HIV-1 exacerbates Mtb's effects on the BBB and CNS cells, worsening TBM pathogenesis.
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