Macrophage adaptation to hypoxia in the tuberculous granuloma potentiates mycobacterium-induced mitochondrial damage and granuloma necrosis

ABSTRACT Granulomas, organized macrophage-rich aggregates, are pathological hallmarks of tuberculosis. Characteristically, as Mycobacterium tuberculosis replicates within macrophages, the granuloma enlarges, and then the center undergoes necrosis, promoting mycobacterial growth in the debris (caseum). This sequence results in large, mycobacterium-rich granulomas that can rupture into airways, facilitating disease transmission. Here, using the zebrafish-Mycobacterium marinum tuberculosis model, we find that both stages – granuloma enlargement and necrosis – depend on the mycobacterial virulence factor, EsxA, that induces mitochondrial damage and apoptosis of infected macrophages. Initially, dying macrophages are engulfed by newly recruited macrophages. Then, the enlarging granuloma core becomes hypoxic and induces Hypoxia Inducible Factor-1 (HIF-1). HIF-1 suppresses mitochondrial respiration, sensitizing macrophages to EsxA mitotoxicity. These sensitized macrophages undergo accelerated apoptosis which outstrips clearance, causing mycobacterium-rich necrotic debris to accumulate in the granuloma cores. Thus, tuberculosis transmission depends on the dynamic interplay between a mycobacterial virulence factor and an adaptive host metabolic program.