Granuloma-like structures in tuberculosis a critical review of their biology, quantitative behavior, and translational use
Abstract
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.
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BibTeX
@article{mastrostefano2026granulomalike,
title = {{Granuloma-like structures in tuberculosis a critical review of their biology, quantitative behavior, and translational use}},
author = {Enrico Mastrostefano and Giovanni Delogu and Alessandro Stamilla and Greta Segafreddo and Ivana Palucci and Giulia Degiacomi and Francesca Boldrin and Alessandro Ravoni and Davide Moretti and Elia Onofri and Michael Dal Molin and Jan Rybniker and Davide Sorze and Enrica Campagnaro and Laura Cioetto-Mazzabò and Paolo Tieri and Santiago Ramón-García and Maria Rosalia Pasca and Riccardo Manganelli},
journal = {FEMS Microbiology Reviews},
year = {2026},
month = oct,
doi = {10.1093/femsre/fuag053},
url = {https://doi.org/10.1093/femsre/fuag053},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Granuloma-like structures in tuberculosis a critical review of their biology, quantitative behavior, and translational use
AU - Enrico Mastrostefano
AU - Giovanni Delogu
AU - Alessandro Stamilla
AU - Greta Segafreddo
AU - Ivana Palucci
AU - Giulia Degiacomi
AU - Francesca Boldrin
AU - Alessandro Ravoni
AU - Davide Moretti
AU - Elia Onofri
AU - Michael Dal Molin
AU - Jan Rybniker
AU - Davide Sorze
AU - Enrica Campagnaro
AU - Laura Cioetto-Mazzabò
AU - Paolo Tieri
AU - Santiago Ramón-García
AU - Maria Rosalia Pasca
AU - Riccardo Manganelli
PY - 2026
DA - 2026/10/21
JO - FEMS Microbiology Reviews
DO - 10.1093/femsre/fuag053
UR - https://doi.org/10.1093/femsre/fuag053
AB - 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.
SN - 0168-6445
SN - 1574-6976
ER -