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

André Kübler, Brian Luna, Christer Larsson, Nicole Ammerman, Bruno B. Andrade, Marlene Orandle, Kevin W. Bock, Ziyue Xu, Ulas Bagci, Daniel J. Molura, John Marshall, Jay Burns, Kathryn Winglee, Bintou Ahmadou Ahidjo, Laurene S. Cheung, Mariah Klunk, Sanjay Jain, Nathella Pavan Kumar, Subash Babu, Alan SherJon S. Friedland, Paul T G Elkington, William Ramses Bishai

Research output: Contribution to journalArticle

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%).

Original languageEnglish (US)
Pages (from-to)431-444
Number of pages14
JournalJournal of Pathology
Volume235
Issue number3
DOIs
StatePublished - Feb 1 2015

Fingerprint

Matrix Metalloproteinases
Matrix Metalloproteinase 1
Mycobacterium tuberculosis
Tuberculosis
Lung
Tissue Inhibitor of Metalloproteinase-3
Pathology
Latent Tuberculosis
Lung Diseases
Tomography
Anti-Bacterial Agents
Rabbits
Morbidity
Mortality
Therapeutics

Keywords

  • Cavity
  • Computed tomography
  • Matrix metalloproteinase
  • Tuberculosis

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Mycobacterium tuberculosis dysregulates MMP/TIMP balance to drive rapid cavitation and unrestrained bacterial proliferation. / Kübler, André; Luna, Brian; Larsson, Christer; Ammerman, Nicole; Andrade, Bruno B.; Orandle, Marlene; Bock, Kevin W.; Xu, Ziyue; Bagci, Ulas; Molura, Daniel J.; Marshall, John; Burns, Jay; Winglee, Kathryn; Ahidjo, Bintou Ahmadou; Cheung, Laurene S.; Klunk, Mariah; Jain, Sanjay; Kumar, Nathella Pavan; Babu, Subash; Sher, Alan; Friedland, Jon S.; Elkington, Paul T G; Bishai, William Ramses.

In: Journal of Pathology, Vol. 235, No. 3, 01.02.2015, p. 431-444.

Research output: Contribution to journalArticle

Kübler, A, Luna, B, Larsson, C, Ammerman, N, Andrade, BB, Orandle, M, Bock, KW, Xu, Z, Bagci, U, Molura, DJ, Marshall, J, Burns, J, Winglee, K, Ahidjo, BA, Cheung, LS, Klunk, M, Jain, S, Kumar, NP, Babu, S, Sher, A, Friedland, JS, Elkington, PTG & Bishai, WR 2015, 'Mycobacterium tuberculosis dysregulates MMP/TIMP balance to drive rapid cavitation and unrestrained bacterial proliferation', Journal of Pathology, vol. 235, no. 3, pp. 431-444. https://doi.org/10.1002/path.4432
Kübler, André ; Luna, Brian ; Larsson, Christer ; Ammerman, Nicole ; Andrade, Bruno B. ; Orandle, Marlene ; Bock, Kevin W. ; Xu, Ziyue ; Bagci, Ulas ; Molura, Daniel J. ; Marshall, John ; Burns, Jay ; Winglee, Kathryn ; Ahidjo, Bintou Ahmadou ; Cheung, Laurene S. ; Klunk, Mariah ; Jain, Sanjay ; Kumar, Nathella Pavan ; Babu, Subash ; Sher, Alan ; Friedland, Jon S. ; Elkington, Paul T G ; Bishai, William Ramses. / Mycobacterium tuberculosis dysregulates MMP/TIMP balance to drive rapid cavitation and unrestrained bacterial proliferation. In: Journal of Pathology. 2015 ; Vol. 235, No. 3. pp. 431-444.
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AU - Andrade, Bruno B.

AU - Orandle, Marlene

AU - Bock, Kevin W.

AU - Xu, Ziyue

AU - Bagci, Ulas

AU - Molura, Daniel J.

AU - Marshall, John

AU - Burns, Jay

AU - Winglee, Kathryn

AU - Ahidjo, Bintou Ahmadou

AU - Cheung, Laurene S.

AU - Klunk, Mariah

AU - Jain, Sanjay

AU - Kumar, Nathella Pavan

AU - Babu, Subash

AU - Sher, Alan

AU - Friedland, Jon S.

AU - Elkington, Paul T G

AU - Bishai, William Ramses

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N2 - 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%).

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