Mycobacterium tuberculosis dysregulates MMP/TIMP balance to drive rapid cavitation and unrestrained bacterial proliferation.

Kubler, A., Luna, B., Larsson, C., Ammerman, N.C., Andrade, B.B., Orandle, M., Bock, K.W., Xu, Z., Bagci, U., Mollura, D. J., Marshall, J., Burns, J., Winglee, K., Ahidjo, B.A., Cheung, L.S., Klunk, M., Jain, S.K., Kumar, N.P., Babu, S., Sher, A., Friedland, J.S., Elkington, P.T. and Bishai, W.R. (2015) Mycobacterium tuberculosis dysregulates MMP/TIMP balance to drive rapid cavitation and unrestrained bacterial proliferation. The Journal of Pathology, 235 (3), 431-444. (doi:10.1002/path.4432).

Abstract

Active tuberculosis (TB) often presents with advanced pulmonary disease, including irreversible lung damage and cavities. Cavitary pathology contributes to antibiotic failure, transmission, morbidity and mortality. Matrix metalloproteinases (MMPs), in particular MMP-1 are implicated in TB pathogenesis. We explored the mechanisms relating MMP/TIMP imbalance to cavity formation in a modified rabbit model of cavitary TB. Our model results in consistent progression of consolidation to human-like cavities (100% by day 28) with resultant bacillary burdens (>107 CFU/g) far greater than those found in matched granulomatous tissue (105 CFU/g). Using a novel, breath-hold computerized tomography scanning and image analysis protocol. We show that cavities develop rapidly from areas of densely consolidated tissue. Radiological change correlated with a decrease in functional lung tissue as estimated by changes in lung density during controlled pulmonary expansion (R2=0.6356, p?<?0.0001). We demonstrated that the expression of interstitial collagenase (MMP-1) is specifically greater in cavitary compared to granulomatous lesions (p?<?0.01), and that TIMP-3 significantly decreases at the cavity surface. Our findings demonstrate that an MMP-1/TIMP imbalance, is associated with the progression of consolidated regions to cavities containing very high bacterial burdens. Our model provided mechanistic insight, correlating with human disease at the pathological, microbiological and molecular levels,. It also provides a strategy to investigate therapeutics in the context of complex TB pathology. We used these findings to predict a MMP/TIMP balance in active TB; and confirmed this in human plasma, revealing the potential of MMP/TIMP levels as key components of a diagnostic matrix aimed at distinguishing active from latent TB (PPV=92.9%; 95%CI 66.1-99.8%, NPV=85.6%; 95%CI 77.0-91.9%).

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Contributors

Author: P.T. Elkington

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