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Published on: February 28, 2025
Mycobacteria trehalose dimycolate interactions with host Mincle remodel blood-brain barrier junctions for brain
Megan I Hayes1, Sumedha Ravishankar1, Jonathan K Shanahan2
1School of Biological Sciences, University of California, San Diego, La Jolla, CA 92037, USA.
Abstract:
Tuberculous meningitis is unique among bacterial meningitides because it occurs in two temporally separated steps: mycobacteria first invade the brain, then form infected macrophage aggregates called Rich foci, which later erode the meninges. Here, using transparent zebrafish larvae, we detail the first step-brain invasion. We find that whereas elsewhere in the body mycobacteria disseminate within phagocytes, only extracellular mycobacteria reach the brain microvasculature. There, they adhere to the microvascular endothelium and grow into microcolonies. These microcolonies induce endothelial tight junction reorganization, creating transient gaps through which bacteria enter the brain and infect microglia to initiate Rich foci. This reorganization is induced by mycobacterial surface glycolipid trehalose dimycolate interacting with its receptor, Mincle. Strikingly, the pathogens Mycobacterium tuberculosis and Mycobacterium marinum and the saprophyte Mycobacterium smegmatis can all invade the brain via this pathway. Thus, M. tuberculosis initiates meningitis, the deadliest form of tuberculosis, using an ancestral determinant important for environmental fitness.
Insights
Mycobacteria invade the brain through extracellular dissemination and microcolony formation on the endothelium. This process, crucial for tuberculous meningitis, is mediated by trehalose dimycolate and Mincle, and utilized by multiple Mycobacterium species.
Area of Science:
- Neuroscience
- Microbiology
- Immunology
Background:
- Tuberculous meningitis involves a two-step process: initial brain invasion by mycobacteria and subsequent formation of Rich foci.
- Understanding the initial brain invasion mechanism is critical for combating this severe form of tuberculosis.
Purpose of the Study:
- To elucidate the mechanism of initial mycobacterial brain invasion in zebrafish larvae.
- To identify the molecular interactions facilitating bacterial entry into the central nervous system.
Main Methods:
- Utilized transparent zebrafish larvae as a model organism.
- Observed mycobacterial dissemination and interaction with brain microvasculature in vivo.
- Investigated the role of mycobacterial surface glycolipids and host receptors.
Main Results:
- Extracellular mycobacteria, not those within phagocytes, reach the brain microvasculature.
- Mycobacteria adhere to endothelium, form microcolonies, and induce tight junction reorganization.
- Trehalose dimycolate and Mincle mediate bacterial entry and subsequent microglial infection.
- Multiple Mycobacterium species, including M. tuberculosis, M. marinum, and M. smegmatis, use this invasion pathway.
Conclusions:
- Mycobacterium tuberculosis initiates meningitis by exploiting an ancestral pathway involving endothelial interaction and trehalose dimycolate-Mincle signaling.
- This conserved mechanism highlights a common vulnerability across different mycobacterial species for brain invasion.
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