Postdoctoral Fellow Colorado State University Fort Collins, Colorado, United States
Introduction/Rationale: Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a major global health challenge. Granulomas are the hallmark lesions of TB and represent both a host defense mechanism and a permissive niche for bacterial persistence. To define immune features associated with bacterial control versus disease progression, we compared the cellular composition and spatial organization of non-necrotic granulomas in two murine TB models with divergent outcomes: Balb/c mice, which partially control infection, and C3HeB/FeJ mice, which develop high bacterial burdens and progressive pathology.
Methods: Using two seven-plex fluorescence immunohistochemistry panels combined with digital pathology and spatial analysis, we quantified immune cell densities, phenotypic diversity, and cell–cell spatial relationships within granulomas over the course of infection.
Results: Granulomas from Balb/c mice exhibited higher cellular density, greater immune phenotypic diversity, and enhanced spatial proximity between T cells and macrophages, features that correlated with a reduction in pulmonary bacterial burden over time. In contrast, granulomas from C3HeB/FeJ mice were larger, less densely cellular, enriched in neutrophils, and associated with sustained bacterial loads. Notably, granuloma size alone did not predict bacterial control. Instead, differences in immune cell composition and spatial architecture distinguished protective from non-protective granulomas.
Conclusion: Together, these findings identify granuloma cellular organization as a key determinant of TB disease outcome and provide insight into immune mechanisms that may be leveraged for host-directed therapeutic strategies.
