Myeloid growth factors promote resistance to mycobacterial infection by forestalling granuloma necrosis through macrophage replenishment
Pagan, Antonio J
Swaim, Laura E
Lieschke, Graham J
Cell Host & Microbe
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Pagan, A. J., Yang, C., Cameron, J., Swaim, L. E., Ellet, F., Lieschke, G. J., & Ramakrishnan, L. (2015). Myeloid growth factors promote resistance to mycobacterial infection by forestalling granuloma necrosis through macrophage replenishment. Cell Host & Microbe, 18 15-26. https://doi.org/10.1016/j.chom.2015.06.008
The mycobacterial ESX-1 virulence locus accelerates macrophage recruitment to the tuberculous granuloma as it is forming. The newly recruited macrophages phagocytose previously infected macrophages that have undergone apoptosis and thereby provide new bacterial growth niches. Thus, a mycobacterium-driven increase in macrophage demand promotes intracellular bacterial growth in the early granuloma. Granuloma macrophages can then undergo necrosis, releasing the bacteria into the extracellular milieu and potentiating mycobacterial growth yet further. Here, we find that global macrophage deficits can accelerate granuloma necrosis. Reduction in the macrophage supply below a critical threshold prevents granuloma macrophage replenishment to the point where apoptotic macrophages, failing to get engulfed, undergo necrosis. Thus, a reduced macrophage supply can promote extracellular bacterial growth in the granuloma. These findings may explain the susceptibility of humans with mononuclear cytopenias to mycobacterial infections. Conversely, increasing macrophage supply delays granuloma necrosis, suggesting the therapeutic potential of myeloid growth factors in tuberculosis.
This work was funded by grants from the National Institutes of Health (T32-AI055396, A.J.P.; A154503 and A136396, L.R.) and the National Health and Medical Research Council (637394, 1044754, and 1069284, G.J.L.), a post-doctoral fellowship from the Taiwan National Science Council (NSC97-2917-I-564-109, C-T.Y.), and an Australian Postgraduate Award and Walter and Eliza Hall Institute of Medical Research Edith Moffatt Scholarship (F.E.). The Australian Regenerative Medicine Institute is supported by funds from the State Government of Victoria and the Australian Federal Government. L.R. is a recipient of the NIH Director’s Pioneer Award and a Wellcome Trust Principal Research Fellowship.
WELLCOME TRUST (103950/Z/14/Z)
External DOI: https://doi.org/10.1016/j.chom.2015.06.008
This record's URL: https://www.repository.cam.ac.uk/handle/1810/248738
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/