Abstract
Tuberculosis (TB) remains a global health pandemic. Infection is spread by the aerosol route and Mycobacterium tuberculosis must drive lung destruction to be transmitted to new hosts. Such inflammatory tissue damage is responsible for morbidity and mortality in patients. The underlying mechanisms of matrix destruction in TB remain poorly understood but consideration of the lung extracellular matrix predicts that matrix metalloproteinases (MMPs) will play a central role, owing to their unique ability to degrade fibrillar collagens and other matrix components. Since we proposed the concept of a matrix degrading phenotype in TB a decade ago, diverse data implicating MMPs as key mediators in TB pathology have accumulated. We review the lines of investigation that have indicated a critical role for MMPs in TB pathogenesis, consider regulatory pathways driving MMPs and propose that inhibition of MMP activity is a realistic goal as adjunctive therapy to limit immunopathology in TB.
Highlights
Tuberculosis (TB) remains a global health pandemic
We review the lines of investigation that have indicated a critical role for matrix metalloproteinases (MMPs) in TB pathogenesis, consider regulatory pathways driving MMPs and propose that inhibition of MMP activity is a realistic goal as adjunctive therapy to limit immunopathology in TB
Mice do not express an orthologue of human MMP-1 in the lung [51, 52], and given that both human and primate studies suggest that this collagenase may be the dominant enzyme driving matrix destruction, the standard C57BL6 mouse model of TB may have limited use to dissect the role of MMPs in TBdriven immunopathology
Summary
Centimetres across, so there must be very extensive lung matrix destruction for such cavitation to occur. Mice do not express an orthologue of human MMP-1 in the lung [51, 52], and given that both human and primate studies suggest that this collagenase may be the dominant enzyme driving matrix destruction, the standard C57BL6 mouse model of TB may have limited use to dissect the role of MMPs in TBdriven immunopathology. In a microarray analysis comparing macrophages from patients with pulmonary TB, TB meningitis and latently infected controls, MMP-1 emerges as the most highly divergently regulated gene, being 256-fold more strongly upregulated in patients with pulmonary TB compared to controls [55] This implies that a tissue destructive innate immune response results in a greater risk of developing active TB, this was not commented on by the authors. MMP-1 and -9 seem to be emerging as key MMPs in TB, consistent with data from more targeted approaches
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