The immunometabolic topography of cellular organization and bacterial control in tuberculosis granulomas

Despite being heavily infiltrated by immune cells, tuberculosis (TB) granulomas often subvert the host response to Mycobacterium tuberculosis (Mtb) infection and support bacterial persistence. Human TB granulomas are enriched for immunosuppressive factors typically associated with tumor-immune evasion, raising the possibility that they promote tolerance to infection. Here we identify candidate drivers for establishing this tolerogenic niche and show that the magnitude of this response correlates with bacterial persistence. We conducted a multimodal spatial analysis of 52 granulomas from 16 nonhuman primates infected with low-dose Mtb for 9-12 weeks. Each granuloma's bacterial burden was quantified individually, enabling us to assess how granuloma spatial structure and function relate to infection control. We found that a universal feature of TB granulomas is partitioning of the myeloid core into two distinct metabolic environments, one of which is hypoxic. This hypoxic environment is associated with pathological immune cell states, dysfunctional cellular organization of the granuloma, and a near-complete blockade of lymphocyte infiltration that would be required for a successful host response. The extent of these hypoxia-associated features correlates with higher bacterial burden. We conclude that hypoxia correlates with immune cell state and organization within granulomas and might subvert immunity to TB.