Mycobacterium tuberculosis invasion and traversal across an in vitro human blood-brain barrier as a pathogenic mechanism for central nervous system tuberculosis

J Infect Dis. 2006 May 1;193(9):1287-95. doi: 10.1086/502631. Epub 2006 Mar 28.


Background: Central nervous system (CNS) tuberculosis is a serious, often fatal disease that disproportionately affects young children. It is thought to develop when Mycobacterium tuberculosis breaches the blood-brain barrier (BBB), which is composed of tightly apposed brain microvascular endothelial cells. However, the mechanism(s) involved in this process are poorly understood.

Methods: To better understand these processes, we developed an in vitro model of M. tuberculosis BBB infection using primary human brain microvascular endothelial cells.

Results: M. tuberculosis was found to both invade and traverse the model BBB significantly more than did M. smegmatis (a nonpathogenic mycobacterium). Invasion by M. tuberculosis across the BBB required host-cell actin cytoskeletal rearrangements. By microarray expression profiling, we found 33 M. tuberculosis genes to be highly up-regulated during the early stages of invasion of the BBB by M. tuberculosis; 18 of them belong to a previously described in vivo-expressed genomic island (Rv0960-Rv1001). Defined M. tuberculosis isogenic transposon mutants for the up-regulated genes Rv0980c, Rv0987, Rv0989c, and Rv1801 were found to be deficient in their ability to invade the BBB model.

Conclusions: We developed an in vitro model of M. tuberculosis BBB infection and identified M. tuberculosis genes that may be involved in CNS invasion.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / analysis
  • Blood-Brain Barrier / microbiology*
  • Brain / blood supply
  • Brain / microbiology
  • Brain / ultrastructure
  • Capillaries / cytology
  • Capillaries / microbiology
  • Cells, Cultured
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / microbiology
  • Gene Expression
  • Genes, Bacterial
  • Humans
  • Models, Biological
  • Mutation
  • Mycobacterium tuberculosis / genetics*
  • Mycobacterium tuberculosis / pathogenicity*
  • Mycobacterium tuberculosis / ultrastructure
  • Tuberculosis, Central Nervous System / genetics*
  • Tuberculosis, Central Nervous System / microbiology*
  • Tuberculosis, Central Nervous System / pathology
  • Virulence / genetics


  • Actins