Granuloma-Like Structures in Tuberculosis A Critical Review of Their Biology, Quantitative Behavior, and...

Tuberculosis (TB) granulomas are complex multicellular structures central to disease pathogenesis and treatment challenges, notably due to bacterial persistence and immune modulation. Existing animal and in vitro models do not fully capture granuloma heterogeneity and immune complexity. Here, we review the biology and applications of Granuloma-Like Structures (GLS) derived from human peripheral blood mononuclear cells infected with Mycobacterium tuberculosis, which recapitulate key features of early granuloma formation, including macrophage differentiation, lymphocyte involvement, and cytokine dynamics. Quantitative analysis identifies conserved bacterial growth trajectories and recurrent aggregate sizes, despite protocol diversity and donor variability. Furthermore, a minimal theoretical model illustrates how aggregate size may influence drug efficacy, through physical and biological mechanisms. Although underutilized in drug screening, GLS offer a promising intermediate platform by bridging simple cell monolayers to animal models, particularly for evaluating host-directed therapies. Standardized metrics and integration with computational models are needed to enhance reproducibility and translational relevance. GLS thus represent a valuable tool to investigate host-pathogen interactions and advance TB drug development under controlled immune conditions.