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 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
Volume20
Issue number9
DOIs
Publication statusPublished - 1 Sep 2018

Cite this

@article{d3873464623c4288bf1c4053a54777a9,
title = "Mycobacteria employ two different mechanisms to cross the blood-brain barrier",
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 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.",
keywords = "Blood-brain barrier, ESX-1 secretion, Trojan horse mechanism, Tuberculosis, Tuberculous meningitis, Zebrafish",
author = "{van Leeuwen}, {Lisanne M.} and Maikel Boot and Coen Kuijl and Picavet, {Daisy I.} and {van Stempvoort}, Gunny and {van der Pol}, {Susanne M.A.} and {de Vries}, {Helga E.} and {van der Wel}, {Nicole N.} and {van der Kuip}, Martijn and {van Furth}, {A. Marceline} and {van der Sar}, {Astrid M.} and Wilbert Bitter",
year = "2018",
month = "9",
day = "1",
doi = "10.1111/cmi.12858",
language = "English",
volume = "20",
journal = "Cellular Microbiology",
issn = "1462-5814",
publisher = "Wiley-Blackwell",
number = "9",

}

Mycobacteria employ two different mechanisms to cross the blood-brain barrier. / van Leeuwen, Lisanne M.; Boot, Maikel; Kuijl, Coen; Picavet, Daisy I.; van Stempvoort, Gunny; van der Pol, Susanne M.A.; de Vries, Helga E.; van der Wel, Nicole N.; van der Kuip, Martijn; van Furth, A. Marceline; van der Sar, Astrid M.; Bitter, Wilbert.

In: Cellular Microbiology, Vol. 20, No. 9, e1285820, 01.09.2018.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Mycobacteria employ two different mechanisms to cross the blood-brain barrier

AU - van Leeuwen, Lisanne M.

AU - Boot, Maikel

AU - Kuijl, Coen

AU - Picavet, Daisy I.

AU - van Stempvoort, Gunny

AU - van der Pol, Susanne M.A.

AU - de Vries, Helga E.

AU - van der Wel, Nicole N.

AU - van der Kuip, Martijn

AU - van Furth, A. Marceline

AU - van der Sar, Astrid M.

AU - Bitter, Wilbert

PY - 2018/9/1

Y1 - 2018/9/1

N2 - 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.

AB - 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.

KW - Blood-brain barrier

KW - ESX-1 secretion

KW - Trojan horse mechanism

KW - Tuberculosis

KW - Tuberculous meningitis

KW - Zebrafish

UR - http://www.scopus.com/inward/record.url?scp=85047720890&partnerID=8YFLogxK

U2 - 10.1111/cmi.12858

DO - 10.1111/cmi.12858

M3 - Article

VL - 20

JO - Cellular Microbiology

JF - Cellular Microbiology

SN - 1462-5814

IS - 9

M1 - e1285820

ER -