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Abstract
Granulomas, organized aggregates of immune cells, form in response to persistent stimuli
and are hallmarks of tuberculosis. Tuberculous granulomas have long been considered
host-protective structures formed to contain infection. However, work in zebrafish
infected with Mycobacterium marinum suggests that granulomas contribute to early bacterial
growth. Here we use quantitative intravital microscopy to reveal distinct steps of
granuloma formation and assess their consequence for infection. Intracellular mycobacteria
use the ESX-1/RD1 virulence locus to induce recruitment of new macrophages to, and
their rapid movement within, nascent granulomas. This motility enables multiple arriving
macrophages to efficiently find and phagocytose infected macrophages undergoing apoptosis,
leading to rapid, iterative expansion of infected macrophages and thereby bacterial
numbers. The primary granuloma then seeds secondary granulomas via egress of infected
macrophages. Our direct observations provide insight into how pathogenic mycobacteria
exploit the granuloma during the innate immune phase for local expansion and systemic
dissemination.