PUBLICATION

Tuberculous Granuloma Induction via Interaction of a Bacterial Secreted Protein with Host Epithelium

Authors
Volkman, H.E., Pozos, T.C., Zheng, J., Davis, J.M., Rawls, J.F., and Ramakrishnan, L.
ID
ZDB-PUB-091221-10
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
Datasets
GEO:GSE8846, GEO:GSE8327
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
Abstract
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.
Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping