Monocyte metabolism reveals latent versus active tuberculosis

Tuberculosis remains a global health challenge, and the way the immune system responds to Mycobacterium tuberculosis (Mtb) can determine whether someone controls infection or develops active disease. Monocytes, a type of white blood cell circulating in the blood, are central to that defense, but until now their detailed functional and metabolic states in people with latent TB infection (TBI), active TB disease (TBD), or no infection (healthy controls, HC) were not well defined. Gráinne Jameson and colleagues set out to fill that gap by comparing circulating monocytes across these groups and by looking at whether treatment changes those cells. They focused on both how monocytes behave—what surface markers they display and what signals they release—and how they make energy, because emerging work suggests immunometabolic dysfunction may underlie ineffective responses in TB. To capture this complexity the team examined peripheral blood monocytes from treatment-naïve and treated individuals, looking for differences that could explain why some people keep infection controlled while others progress to disease.

The researchers used high-dimensional flow cytometry, Luminex cytokine/chemokine assays, and SCENITH™ (a flow-based metabolic assay) to profile unstimulated and Mtb-stimulated monocytes. Their analysis revealed clear, measurable differences. Compared with healthy controls, monocytes from both TBI and TBD showed higher levels of CD14 and CD45RA. HLA-DR, a marker associated with antigen presentation, was lower in TBI than in HC and fell further in TBD. TNF receptors were specifically downregulated in TBI but remained unchanged in TBD. Looking at cytokines and chemokines, baseline profiles in TBI and TBD were similar to each other and distinct from HC, yet when monocytes were challenged with Mtb the TBI cells mounted a stronger cytokine response than those from TBD. Metabolically, monocytes from both TBI and TBD relied more on glycolysis and less on mitochondrial function than those from HC, but treatment partially restored mitochondrial dependence. After Mtb challenge, TBI monocytes showed greater glycolytic capacity than TBD monocytes.

Together, these findings indicate that circulating monocytes carry both phenotypic and metabolic signatures that differentiate latent infection from active TB, and that some of these features are at least partially reversible with treatment. The contrast—reprogrammed, adaptable glycolytic profiles in TBI versus impaired metabolic adaptability in TBD—suggests that dysfunctional myeloid activation accompanies active disease. Because these differences were measurable in blood monocytes, the work points to circulating monocyte metabolism and cytokine responses as potential biomarkers to distinguish latent and active TB and to monitor treatment effects. It also raises the possibility that targeting monocyte metabolism could be explored as a therapeutic strategy, though the study itself reports observations rather than testing interventions. Overall, the results underscore the value of combining phenotypic, functional, and metabolic assays to understand TB immunity and to identify measurable signals that reflect disease status.