Mucosal BCG vaccination reprograms lung interstitial macrophages and enhances antimicrobial defense in mice.

Summary

Using multiple BCG administration routes and integrated cellular and spatial profiling, the study showed that intratracheal BCG preferentially reprograms lung interstitial macrophages rather than alveolar macrophages. These interstitial macrophages formed organized immune hubs with CD4 T cells, and intratracheal vaccination provided superior protection against both Mycobacterium tuberculosis and the heterologous pathogen Pseudomonas aeruginosa.

Key Findings

• Intratracheal BCG preferentially reprogrammed lung interstitial macrophages, whereas intravenous BCG mainly remodeled alveolar macrophages.
• Intratracheal BCG induced spatially organized immune hubs containing interstitial macrophages and CD4 T cells.
• Intratracheal BCG provided superior protection against Mycobacterium tuberculosis and Pseudomonas aeruginosa in mice.

Clinical Implications

The findings support further development of intranasal or inhaled tuberculosis vaccines and other mucosal vaccines that deliberately target lung interstitial macrophage programs. Translation to humans will require confirmation of macrophage subset biology, dose, safety, and protection in clinical studies.

Limitations

• The study was performed in mice, and the total number of animals was not provided in the abstract.
• The abstract does not establish whether the identified macrophage programs and protection translate directly to humans.

Future Directions

Future work should define the molecular signals that reprogram interstitial macrophages, determine the durability and breadth of mucosal protection, and test intranasal or inhaled BCG-based strategies in human translational studies.