Bacteria load and hypoxia contribute to glucose uptake by macrophages and T cells in cynomolgus macaque granulomas

Abstract

Granulomas form during tuberculosis (TB) and restrain bacterial dissemination but are also sites of mycobacterial replication and persistence. The immunometabolic state of cells in granulomas has immunologic and diagnostic relevance and PET-CT with the glucose analog FDG demonstrates that granuloma glucose uptake is dynamic and heterogenous within a host. Basic details on glucose uptake, including the cells responsible for FDG PET signal, have not been resolved and filling these gaps will improve interpretation of PET data in TB. Our objective was to identify relationships between glucose (FDG) uptake and granuloma composition and to identify factors that drive this process in M. tuberculosis-infected cynomolgus macaques. We used glucose transporter 1 (GLUT1) to identity cells that may be using glucose as an energy source in granulomas, and compared these data with the cell’s microenvironment, and the granuloma’s bacteria load and FDG PET data to determine how these factors influence GLUT1 expression. We found that GLUT1 was strongly expressed by myeloid cell subsets in specific granuloma microenvironments and this pattern was conserved in granulomas from different organs. We also identified macrophage subsets and T cells that may be important contributors to a granuloma’s potential glucose (FDG) uptake when their GLUT1 expression and population sizes were considered. We also correlated granuloma bacteria loads and hypoxia with GLUT1 expression, suggesting that bacterial antigens and hypoxic conditions drive a granuloma’s glucose uptake. Taken together, our data suggest that granuloma glycolysis and FDG uptake are driven, in part, by cell subset-specific responses to a granuloma’s microbial and microenvironmental milieu. This work was supported by NIH grants AI134183 and AI118195.