(A) Macrophages infected with ESX-1–replete mycobacteria signal to recruit uninfected macrophages to the surrounding area (i), including in close proximity to the initially infected macrophage (ii). After intracellular replication, ESX-1–replete bacteria spread to the closely apposed, newly recruited macrophages, with or without lysis of the initially infected macrophage (iii). After spread to the newly recruited macrophages (and dendritic cells), the mycobacteria replicate further (iv), to sustain the cycle of cell-to-cell spread until the onset of adaptive immunity. (B) ESX-1–deficient mycobacteria are defective in the ability to recruit uninfected macrophages and to form aggregates with the initially infected cell and in the ability to spread to adjacent cells. As a consequence, ESX-1–deficient mycobacteria are less efficient in expanding the size of the pool of infected cells but replicate efficiently in the initially infected cells.