From Bacterial Persistence to Granuloma Failure: Mechanisms of LTBI Reactivation as a Framework for Tuberculosis Prevention and Treatment

Latent tuberculosis infection constitutes the principal reservoir from which tuberculosis (TB) disease emerges, yet the molecular transition from durable containment to reactivation remains incompletely resolved. Reactivation is not a single bacterial “awakening” event or a nonspecific consequence of immunosuppression. Instead, we propose a hypothesis-generating threshold framework across an interconnected pathogen–host–microenvironment system. This narrative review integrates evidence on Mycobacterium tuberculosis persistence and resuscitation programs, including metabolic remodeling, resuscitation-promoting factors, cell-wall turnover, and metal acquisition, with defects in adaptive and innate immunity, immunometabolic control, cytokine networks, aging, comorbid disease, and epigenetic regulation. We further examine the granuloma as a spatially heterogeneous ecosystem in which hypoxia, necrosis, vascular dysfunction, fibrosis, extracellular-vesicle communication, and intercellular crosstalk may influence bacterial control. Evidence from human longitudinal and cross-sectional studies is distinguished from non-human-primate, other animal, in vitro, and cross-system evidence. The proposed balance between bacillary resuscitation potential and local containment capacity has not been prospectively validated in humans or defined by a numerical clinical cutoff. Pathogen-, host-, and lesion-directed approaches are therefore discussed as research priorities. They are not alternatives to recommended TB preventive treatment for eligible individuals or antimicrobial treatment of TB disease. Prospective human validation is required before the framework can inform biomarker-guided intervention or patient stratification.