Spatially-distinct programming of macrophage diversity within the granulomas of Mycobacterium tuberculosis infected...

Area of Science:

• Immunology
• Cell Biology
• Infectious Diseases

Background:

• Tuberculosis (TB) pathogenesis involves granulomas, where macrophages play a critical role.
• The diversity and function of macrophages in TB lesions remain incompletely understood.
• Understanding macrophage heterogeneity is key to developing effective TB immunotherapies.

Purpose of the Study:

• To profile macrophage subsets within lung granulomas during early TB.
• To investigate the spatial distribution and infection susceptibility of different macrophage types.
• To identify molecular pathways exploited by Mycobacterium tuberculosis (Mtb) within host macrophages.

Main Methods:

• Single-cell RNA sequencing of lung tissue and granulomas from a nonhuman primate TB model.
• Immunofluorescence staining to determine macrophage localization and phenotype.
• Comparative gene expression analysis between infected and uninfected macrophages.

Main Results:

• Identified distinct macrophage subsets, including embryonic-origin tissue-resident alveolar macrophages and monocyte-derived macrophages, with specific granuloma localization.
• Tissue-resident alveolar macrophages and a subset undergoing epithelial-to-mesenchymal transition showed the highest Mtb burden.
• Infected macrophages displayed altered expression of immune and migration genes, suggesting Mtb manipulation for survival.

Conclusions:

• Macrophage heterogeneity significantly influences susceptibility to Mtb infection.
• Distinct macrophage subsets have differential roles in TB granuloma formation and bacterial containment.
• Findings provide insights into potential immunomodulatory targets for TB treatment.