Towards host-directed therapy: The role of matrix metalloproteinases in the immunopathogenesis of tuberculosis.

Matrix metalloproteinases (MMPs) are zinc-dependent proteases that sit at the interface of inflammation, tissue injury, and repair in tuberculosis. In pulmonary tuberculosis, dysregulated MMP activity drives extracellular matrix degradation, cavitation, and remodelling that contribute to post-tuberculosis lung disease. In tuberculous meningitis, MMPs have been implicated in blood-brain barrier disruption and neuroinflammatory injury. Experimental and clinical research consistently link elevated MMPs with radiological damage and adverse outcomes, while mechanistic studies highlight the importance of cellular networks in amplifying matrix-destructive pathways. MMP activity is further shaped by host modifiers, such as co-infection, and the pathological microenvironment characterised by metabolic stress, acidosis and hypoxia. Host-directed therapies are interventions that target dysregulated host immune and tissue injury pathways, rather than Mycobacterium tuberculosis itself, with the aim of limiting pathology and improving clinical outcomes. Preclinical evidence supports modulation of matrix degradation, exemplified by doxycycline-mediated suppression of pathological MMP activity and improved survival in selected pulmonary and central nervous system TB models. Future progress will depend on translating these insights into clinical benefit with carefully designed studies that consider host heterogeneity, co-infection, and disease compartment to refine matrix-targeted host-directed approaches in an era of increasingly personalised medicine.