Mycobacterium tuberculosis dysregulates MMP/TIMP balance to drive rapid cavitation and unrestrained bacterial proliferation
The Journal of Pathology, 235(3), 431–444
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 resulted 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 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 (R2 = 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
Abstract sourceThis 2015 study examined how matrix metalloproteinase and tissue inhibitor imbalances relate to lung cavity formation in a rabbit model of tuberculosis, using computed tomography and human plasma samples.
Summary
The study investigated how an imbalance between matrix metalloproteinases (MMPs), enzymes that break down extracellular matrix, and tissue inhibitors of metalloproteinases (TIMPs) relates to tuberculosis-associated lung cavity formation. In a rabbit model, the authors used computed tomography and image analysis to track disease progression, and compared MMP/TIMP patterns in cavitary and granulomatous tissue. They also assessed plasma samples from people with active or latent tuberculosis and healthy controls.
The authors reported that consolidated lung regions progressed to cavities in the rabbit model, with higher bacterial burdens in cavitary tissue than in matched granulomatous tissue. MMP-1 expression was higher in cavitary lesions, while TIMP-3 decreased at cavity surfaces. In human plasma, a combination of MMP/TIMP measurements showed potential for distinguishing active from latent tuberculosis in the studied samples. These findings concern an animal model and an exploratory human-sample analysis; they do not establish clinical diagnostic readiness.
Cite this work
André Kübler, Brian Luna, Christer Larsson, Nicole C Ammerman, Bruno B Andrade, Marlene Orandle, Kevin W Bock, Ziyue Xu, Ulas Bagci, Daniel J Mollura, John Marshall, Jay Burns, Kathryn Winglee, Bintou Ahmadou Ahidjo, Laurene S Cheung, Mariah Klunk, Sanjay K Jain, Nathella Pavan Kumar, Subash Babu, Alan Sher, Jon S Friedland, Paul T G Elkington, William R Bishai (2015). Mycobacterium tuberculosis dysregulates MMP/TIMP balance to drive rapid cavitation and unrestrained bacterial proliferation. The Journal of Pathology, 235(3), 431–444 https://doi.org/10.1002/path.4432
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