Multimodal profiling of lung granulomas reveals cellular correlates of tuberculosis control

Mycobacterium tuberculosis lung infection results in a complex multicellular structure, the granuloma. In some granulomas, immune activity promotes bacterial clearance; in others, bacteria persist and grow. We identified correlates of bacterial control in cynomolgus macaque granulomas by co-registering longitudinal PET-CT imaging, single-cell RNA-sequencing, and measures of bacterial clearance. Bacterial control associates with the dynamics of granuloma formation and cellular composition. Early granulomas have limited capacity for bacterial restriction and are characterized by Type 2 immune features—plasma cells, mast cells, and IL-4/13 signaling. Granulomas that emerge after the onset of adaptive responses exhibit superior bacterial killing and are enriched for hybrid Type1-Type17 and certain cytotoxic T cells—host immune targets that can be leveraged to develop new vaccine and therapeutic strategies for TB. One-Sentence Summary Bacterial control in TB lung granulomas correlates with the timing of granuloma formation and the cellular immune environment. ### Competing Interest Statement A.K.S. reports compensation for consulting and/or SAB membership from Merck, Honeycomb Biotechnologies, Cellarity, Cogen Therapeutics, Ochre Bio, and Dahlia Biosciences. CL: shareholder and consultant Honeycomb biotechnologies. TKH: shareholder and consultant nference, inc