ZFIN ID: ZDB-PUB-091221-10
Tuberculous Granuloma Induction via Interaction of a Bacterial Secreted Protein with Host Epithelium
Volkman, H.E., Pozos, T.C., Zheng, J., Davis, J.M., Rawls, J.F., and Ramakrishnan, L.
Date: 2010
Source: Science (New York, N.Y.)   327(5964): 466-469 (Journal)
Registered Authors: Davis, James M., Pozos, Tamara Christine, Ramakrishnan, Lalita, Rawls, John F., Volkman, Hannah, Zheng, John
Keywords: none
Microarrays: GEO:GSE8327, GEO:GSE8846
MeSH Terms:
  • Animals
  • Antigens, Bacterial/genetics
  • Antigens, Bacterial/metabolism*
  • Bacterial Proteins/genetics
  • Bacterial Proteins/metabolism*
  • Disease Models, Animal
  • Embryo, Nonmammalian/microbiology
  • Enzyme Induction
  • Epithelial Cells/enzymology*
  • Granuloma/metabolism
  • Granuloma/microbiology*
  • Macrophages/microbiology
  • Macrophages/physiology
  • Matrix Metalloproteinase 9/genetics
  • Matrix Metalloproteinase 9/metabolism*
  • Mycobacterium Infections, Nontuberculous/microbiology*
  • Mycobacterium marinum/growth & development
  • Mycobacterium marinum/metabolism
  • Mycobacterium marinum/pathogenicity*
  • Mycobacterium tuberculosis/genetics
  • Mycobacterium tuberculosis/pathogenicity
  • Oligoribonucleotides, Antisense
  • Recombinant Proteins/metabolism
  • Tuberculosis/microbiology*
  • Virulence Factors/genetics
  • Virulence Factors/metabolism*
  • Zebrafish/embryology
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed: 20007864 Full text @ Science
Granulomas, organized aggregates of immune cells, are a hallmark of tuberculosis, and have traditionally been thought to restrict mycobacterial growth. However, analysis of Mycobacterium marinum in zebrafish has shown that the early granuloma facilitates mycobacterial growth; uninfected macrophages are recruited to the granuloma where they are productively infected by M. marinum. Here, we identified the molecular mechanism by which mycobacteria induce granulomas: the bacterial secreted protein ESAT-6, which has long been implicated in virulence, induced matrix metalloproteinase-9 (MMP9) in epithelial cells neighboring infected macrophages. MMP9 enhanced recruitment of macrophages, which contributed to nascent granuloma maturation and bacterial growth. Disruption of MMP9 function attenuated granuloma formation and bacterial growth. Thus, interception of epithelial MMP9 production could hold promise as a host-targeting tuberculosis therapy.