Matrix metalloproteinases in tuberculosis

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.

Immunity and Immunopathology in the Tuberculous Granuloma

“…The collagenase matrix metalloproteinase-1 (MMP1) has been implicated in the final steps of granuloma cavitation through the degradation of the fibrous extracellular matrix surrounding the granuloma (Fig. 1) (Elkington et al 2011c). SNPs in MMP1 that increase protein abundance or enzymatic activity have been associated with TB hypersusceptibility (Ganachari et al 2010;Wang et al 2010).…”

Heightened Plasma Levels of Heme Oxygenase-1 and Tissue Inhibitor of Metalloproteinase-4 as Well as Elevated Peripheral Neutrophil Counts Are Associated With TB-Diabetes Comorbidity

“…The disease process in pulmonary TB involves enzymatic degradation of lung tissue by MMPs. 12,21,22 This situation is refl ected by the increased MMP levels in patients with TB, which correlate with disease severity. 13 We have recently observed that plasma levels of MMPs and TIMPs are elevated in pediatric patients with TB compared with age-matched healthy children.…”

MMPs are regulatory enzymes in pathways of inflammatory disorders, tissue injury, malignancies and remodelling of the lung

“…The destruction of extracellular matrix by MMPs allows mycobacteria to spread from the interstitium to the airways, and results in cavities with an immunodeficient milieu in which mycobacteria can proliferate as a consequence of a missing protective immune response. These events are initiated by mycobacterial MMP activation within the monocytes/macrophages hosting the mycobacteria in the pulmonary interstitium, as discussed by ELKINGTON et al [6] in a forthcoming article in this series, and elsewhere [7].…”