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
-
- Necrosis/pathology
- Macrophages/immunology*
- Macrophages/microbiology*
- Disease Models, Animal
- Zebrafish
- Host-Pathogen Interactions*
- Apoptosis
- Intercellular Signaling Peptides and Proteins/metabolism*
- Animals
- Granuloma/immunology
- Granuloma/microbiology
- Granuloma/pathology*
- Phagocytosis
- Mycobacterium marinum/growth & development*
- Mycobacterium marinum/immunology*
- PubMed
- 26159717 Full text @ Cell Host Microbe
Citation
Pagán, A.J., Yang, C.T., Cameron, J., Swaim, L.E., Ellett, F., Lieschke, G.J., Ramakrishnan, L. (2015) Myeloid Growth Factors Promote Resistance to Mycobacterial Infection by Curtailing Granuloma Necrosis through Macrophage Replenishment. Cell Host & Microbe. 18:15-26.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping