Immunometabolic Reprogramming of Monocytes in Tuberculosis Infection and Disease

Jameson, G.; Batten, I.; Dyer, A. H.; Geoghegan, C.; Murray, M.; McDonnell, N.; Murphy, D. M.; Connolly, S. A.; McLaughlin, A. M.; O Maoldomhnaigh, C.; Gleeson, L. E.; Keane, J.; Basdeo, S. A.

doi:10.1101/2025.04.24.650431

bioRxiv · 10.1101/2025.04.24.650431

Immunometabolic Reprogramming of Monocytes in Tuberculosis Infection and Disease

Jameson, G.·Batten, I.·Dyer, A. H.·Geoghegan, C.·Murray, M.·McDonnell, N.·Murphy, D. M.·Connolly, S. A.·McLaughlin, A. M.·O Maoldomhnaigh, C.·Gleeson, L. E.·Keane, J.·Basdeo, S. A.

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Abstract

RationaleMonocytes 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. ObjectivesTo 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. MeasurementsPeripheral 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-naive and treated individuals were analysed. Main ResultsMonocytes from TBI and TBD showed distinct phenotypes from HC, marked by elevated CD14 and CD45RA. HLA-DR was reduced in TBI versus HC and further decreased in TBD. 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, 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 TBD. ConclusionsMonocyte metabolic plasticity and cytokine production distinguish latent from active TB and are partially reversible with treatment. Circulating monocyte metabolism reflects TB immune status and may serve as a biomarker or therapeutic target. Reprogrammed glycolytic profiles in TBI contrast with impaired adaptability in TBD, suggesting dysfunctional myeloid activation during disease.

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Jameson, G., Batten, I., Dyer, A. H., Geoghegan, C., Murray, M., McDonnell, N., Murphy, D. M., Connolly, S. A., McLaughlin, A. M., O Maoldomhnaigh, C., Gleeson, L. E., Keane, J., Basdeo, S. A.. 2025-04-26. Immunometabolic Reprogramming of Monocytes in Tuberculosis Infection and Disease. https://doi.org/10.1101/2025.04.24.650431

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