PUBLICATION

Myeloid Growth Factors Promote Resistance to Mycobacterial Infection by Curtailing Granuloma Necrosis through Macrophage Replenishment

Authors
Pagán, A.J., Yang, C.T., Cameron, J., Swaim, L.E., Ellett, F., Lieschke, G.J., Ramakrishnan, L.
ID
ZDB-PUB-150711-2
Date
2015
Source
Cell Host & Microbe   18: 15-26 (Journal)
Registered Authors
Cameron, James, Ellett, Felix, Ramakrishnan, Lalita, Yang, Chao-Tsung
Keywords
none
MeSH Terms
  • Animals
  • Apoptosis
  • Disease Models, Animal
  • Granuloma/immunology
  • Granuloma/microbiology
  • Granuloma/pathology*
  • Host-Pathogen Interactions*
  • Intercellular Signaling Peptides and Proteins/metabolism*
  • Macrophages/immunology*
  • Macrophages/microbiology*
  • Mycobacterium marinum/growth & development*
  • Mycobacterium marinum/immunology*
  • Necrosis/pathology
  • Phagocytosis
  • Zebrafish
PubMed
26159717 Full text @ Cell Host Microbe
Abstract
The mycobacterial ESX-1 virulence locus accelerates macrophage recruitment to the forming tuberculous granuloma. Newly recruited macrophages phagocytose previously infected apoptotic macrophages to become new bacterial growth niches. Granuloma macrophages can then necrose, releasing mycobacteria into the extracellular milieu, which potentiates their growth even further. Using zebrafish with genetic or pharmacologically induced macrophage deficiencies, we find that global macrophage deficits increase susceptibility to mycobacterial infection by accelerating granuloma necrosis. This is because reduction in the macrophage supply below a critical threshold decreases granuloma macrophage replenishment to the point where apoptotic infected macrophages, failing to get engulfed, necrose. Reducing macrophage demand by removing bacterial ESX-1 offsets the susceptibility of macrophage deficits. Conversely, increasing macrophage supply in wild-type fish by overexpressing myeloid growth factors induces resistance by curtailing necrosis. These findings may explain the susceptibility of humans with mononuclear cytopenias to mycobacterial infections and highlight the therapeutic potential of myeloid growth factors in tuberculosis.
Genes / Markers
Figures
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Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes