Human lung organoids model for assessing host response toinfection.

INTRODUCTION: Airway and alveolar epithelial cells serve as the primary defense in the lower respiratory tract, yet their exact role ininfection is incompletely understood. Given thatis a human-restricted pathogen, a representative human model is required. Lung organoids (LOs), which are composed of various epithelial cells, mesenchymal cells, and extracellular matrix, facilitate the investigation of bacterial infections.

METHODS: In this study, we established aninfection model using human induced pluripotent stem cells (iPSCs)-derived LOs.

RESULTS: Prolonged infection led to the gradual invasion offrom the periphery to the interior of the organoid, leading to decreased viability and the induction of fibrotic responses. Transcriptomic and protein analyses suggest that Mtb infection triggered a TLR4/NF-κB-associated inflammatory response. Additionally, the elevation of antimicrobial peptides and the release of diverse pro-inflammatory cytokines and chemokines were noted in the infected LOs.

CONCLUSION: These findings emphasize the potential role of LOs in host defense and demonstrate that the-infected lung organoid model provides a novel platform for elucidating the role of pulmonary structural cells in tuberculosis pathogenesis. Furthermore, this model opens new avenues for the development of molecular therapeutic strategies.