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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. ; 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. ; This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.chom.2015.06.008