Tuberculous granuloma formation is enhanced by a mycobacterium virulence determinant

PLoS Biol. 2004 Nov;2(11):e367. doi: 10.1371/journal.pbio.0020367. Epub 2004 Oct 26.


Granulomas are organized host immune structures composed of tightly interposed macrophages and other cells that form in response to a variety of persistent stimuli, both infectious and noninfectious. The tuberculous granuloma is essential for host containment of mycobacterial infection, although it does not always eradicate it. Therefore, it is considered a host-beneficial, if incompletely efficacious, immune response. The Mycobacterium RD1 locus encodes a specialized secretion system that promotes mycobacterial virulence by an unknown mechanism. Using transparent zebrafish embryos to monitor the infection process in real time, we found that RD1-deficient bacteria fail to elicit efficient granuloma formation despite their ability to grow inside of infected macrophages. We showed that macrophages infected with virulent mycobacteria produce an RD1-dependent signal that directs macrophages to aggregate into granulomas. This Mycobacterium-induced macrophage aggregation in turn is tightly linked to intercellular bacterial dissemination and increased bacterial numbers. Thus, mycobacteria co-opt host granulomas for their virulence.

Publication types

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

MeSH terms

  • Animals
  • Cell Death
  • Cell Line
  • Cells, Cultured
  • Chemotaxis
  • Granuloma / microbiology
  • In Situ Nick-End Labeling
  • Macrophage Activation
  • Macrophages / metabolism
  • Macrophages / microbiology
  • Mice
  • Microscopy, Video
  • Mutation
  • Mycobacterium Infections / microbiology*
  • Mycobacterium Infections / pathology
  • Mycobacterium tuberculosis / pathogenicity*
  • Ranidae / microbiology*
  • Time Factors
  • Tuberculoma / microbiology*
  • Tuberculosis / microbiology*
  • Virulence
  • Zebrafish