Multimodal profiling of lung granulomas in macaques 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, but in others, bacteria persist and grow. We identified correlates of bacterial control in cynomolgus macaque lung granulomas by co-registering longitudinal positron emission tomography and computed tomography imaging, single-cell RNA sequencing, and measures of bacterial clearance. Bacterial persistence occurred in granulomas enriched for mast, endothelial, fibroblast, and plasma cells, signaling amongst themselves via type 2 immunity and wound-healing pathways. Granulomas that drove bacterial control were characterized by cellular ecosystems enriched for type 1-type 17, stem-like, and cytotoxic T cells engaged in pro-inflammatory signaling networks involving diverse cell populations. Granulomas that arose later in infection displayed functional characteristics of restrictive granulomas and were more capable of killing Mtb. Our results define the complex multicellular ecosystems underlying (lack of) granuloma resolution and highlight host immune targets that can be leveraged to develop new vaccine and therapeutic strategies for TB. [Display omitted] •Timing of granuloma formation influences local microenvironment and bacterial burden•Mast cells, type 2 immunity, and tissue remodeling underlie early, high-burden granulomas•Type1-type17 and cytotoxic T cells associate with late-forming, low-burden granulomas•Distinct interaction circuits across granuloma phenotypes nominate therapeutic targets Tuberculosis granulomas exhibit independent trajectories even within a single individual: some granulomas permit high bacterial growth, whereas others successfully resolve. Gideon et al. leveraged longitudinal PET-CT, bacterial burden assays, and scRNA-seq in cynomolgus macaques to define dynamic cellular phenotypes and circuits underlying granuloma persistence and immune control. Uncovered cell states and interactions may represent targets for host-directed therapies and vaccines.