Monocyte Metabolic Plasticity and Cytokine Production Differentiate Latent TB Infection from Active Disease

Rationale:Monocytes are central to host defence against Mycobacterium tuberculosis (Mtb), yet their functional and metabolic profiles during latent TB infection (TBI) and active TB disease (TBD) remain poorly defined.Immunometabolic dysfunction may underlie ineffective responses in TB, but cell-specific mechanisms are unclear. Objectives:To compare the phenotypic, functional, and metabolic profiles of circulating monocytes from individuals with TBI, TBD, and healthy controls (HC), and assess the impact of treatment. Measurements:Peripheral blood monocytes were profiled using high-dimensional flow cytometry, Luminex cytokine/chemokine assays, and SCENITH, a flow-based metabolic assay.Unstimulated and Mtb-stimulated monocytes from treatment-nave and treated individuals were analysed. Main Results:Monocytes from TBI and TBD showed distinct phenotypes from HC, marked by elevated CD14.HLA-DR was reduced in classical monocytes from TBD compared with both TBI and HC.TNF receptors were downregulated in TBI but unchanged in TBD.Baseline cytokine and chemokine profiles in TBI and TBD were similar (yet distinct from HC), but Mtb stimulation elicited a stronger cytokine response in TBI.Metabolically at baseline, TBI and TBD monocytes exhibited increased glycolysis and reduced mitochondrial dependence versus HC.Treatment partially restored mitochondrial function.Upon Mtb challenge, TBI monocytes had higher glycolytic capacity than HC and TBD.