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Mycobacterium tuberculosis dysregulates MMP / TIMP balance to drive rapid cavitation and unrestrained bacterial proliferation
Author(s) -
Kübler André,
Luna Brian,
Larsson Christer,
Ammerman Nicole C,
Andrade Bruno B,
Orandle Marlene,
Bock Kevin W,
Xu Ziyue,
Bagci Ulas,
Mollura Daniel J,
Marshall John,
Burns Jay,
Winglee Kathryn,
Ahidjo Bintou Ahmadou,
Cheung Laurene S,
Klunk Mariah,
Jain Sanjay K,
Kumar Nathella Pavan,
Babu Subash,
Sher Alan,
Friedland Jon S,
Elkington Paul TG,
Bishai William R
Publication year - 2015
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4432
Subject(s) - mycobacterium tuberculosis , matrix metalloproteinase , microbiology and biotechnology , balance (ability) , chemistry , tuberculosis , biology , medicine , biochemistry , pathology , neuroscience
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 resulted in consistent progression of consolidation to human‐like cavities (100% by day 28), with resultant bacillary burdens (>10 7 CFU /g) far greater than those found in matched granulomatous tissue (10 5 CFU /g). Using a novel, breath‐hold computed tomography ( CT ) scanning and image analysis protocol, we showed that cavities developed 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 ( R 2 = 0.6356, p < 0.0001). We demonstrated that the expression of interstitial collagenase ( MMP ‐1) was specifically greater in cavitary compared to granulomatous lesions ( p < 0.01), and that TIMP ‐3 significantly decreased at the cavity surface. Our findings demonstrated 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 provided 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%). Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd