PUBLICATION
Mycobacteria employ two different mechanisms to cross the blood-brain barrier
- Authors
- van Leeuwen, L.M., Boot, M., Kuijl, C., Picavet, D.I., van den Brink, G., van der Pol, S.M.A., de Vries, H.E., van der Wel, N.N., van der Kuip, M., van Furth, A.M., van der Sar, A.M., Bitter, W.
- ID
- ZDB-PUB-180512-5
- Date
- 2018
- Source
- Cellular Microbiology 20(9): e12858 (Journal)
- Registered Authors
- Bitter, Wilbert, van der Sar, Astrid M.
- Keywords
- ESX-1 secretion, Trojan Horse mechanism, Tuberculosis, Tuberculous meningitis, blood-brain barrier, zebrafish
- MeSH Terms
-
- Animals
- Blood-Brain Barrier/microbiology*
- Brain/microbiology
- Central Nervous System Infections/pathology*
- Disease Models, Animal
- Host-Pathogen Interactions*
- Macrophages/microbiology
- Mycobacterium Infections, Nontuberculous/pathology*
- Mycobacterium marinum/growth & development*
- Zebrafish
- PubMed
- 29749044 Full text @ Cell. Microbiol.
Citation
van Leeuwen, L.M., Boot, M., Kuijl, C., Picavet, D.I., van den Brink, G., van der Pol, S.M.A., de Vries, H.E., van der Wel, N.N., van der Kuip, M., van Furth, A.M., van der Sar, A.M., Bitter, W. (2018) Mycobacteria employ two different mechanisms to cross the blood-brain barrier. Cellular Microbiology. 20(9):e12858.
Abstract
Central nervous system (CNS) infection by Mycobacterium tuberculosis is one of the most devastating complications of tuberculosis, in particular in early childhood. In order to induce CNS infection, M. tuberculosis needs to cross specialized barriers protecting the brain. How M. tuberculosis crosses the blood-brain barrier (BBB) and enters the CNS is not well understood. Here, we use transparent zebrafish larvae and the closely related pathogen Mycobacterium marinum to answer this question. We show that in the early stages of development mycobacteria rapidly infect brain tissue, either as free mycobacteria or within circulating macrophages. After the formation of a functionally intact BBB the infiltration of brain tissue by infected macrophages is delayed, but not blocked, suggesting that crossing the BBB via phagocytic cells is one of the mechanisms used by mycobacteria to invade the CNS. Interestingly, depletion of phagocytic cells did not prevent M. marinum from infecting the brain tissue, indicating that free mycobacteria can independently cause brain infection. Detailed analysis showed that mycobacteria are able to cause vasculitis by extracellular outgrowth in the smaller blood vessels and by infecting endothelial cells. Importantly, we could show that this second mechanism is an active process that dependents on an intact ESX-1 secretion system, which extends the role of ESX-1 secretion beyond the macrophage infection cycle.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping