Myeloid growth factors promote resistance to mycobacterial infection by forestalling granuloma necrosis through macrophage replenishment

Abstract

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.