Format

Send to

Choose Destination
Cell Host Microbe. 2015 Jul 8;18(1):15-26. doi: 10.1016/j.chom.2015.06.008.

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

Author information

1
Department of Medicine, University of Cambridge, Cambridge CB2 0QH, UK; Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
2
Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
3
Cancer and Haematology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
4
Cancer and Haematology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia.
5
Department of Medicine, University of Cambridge, Cambridge CB2 0QH, UK; Department of Microbiology, University of Washington, Seattle, WA 98195, USA; Department of Immunology, University of Washington, Seattle, WA 98195, USA; Department of Medicine, University of Washington, Seattle, WA 98195, USA. Electronic address: lr404@cam.ac.uk.

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.

PMID:
26159717
PMCID:
PMC4509513
DOI:
10.1016/j.chom.2015.06.008
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center