Mycobacteria employ two different mechanisms to cross the blood-brain barrier

Lisanne M. van Leeuwen, Maikel Boot, Coen Kuijl, Daisy I. Picavet, Gunny van Stempvoort, Susanne M.A. van der Pol, Helga E. de Vries, Nicole N. van der Wel, Martijn van der Kuip, A. Marceline van Furth, Astrid M. van der Sar, Wilbert Bitter*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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 specialised 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 depends on an intact ESX-1 secretion system, which extends the role of ESX-1 secretion beyond the macrophage infection cycle.

Original languageEnglish
Article numbere1285820
JournalCellular Microbiology
Issue number9
Publication statusPublished - 1 Sep 2018

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