Change search
ReferencesLink to record
Permanent link

Direct link
Mycobacterium tuberculosis dysregulates MMP/TIMP balance to drive rapid cavitation and unrestrained bacterial proliferation.
Johns Hopkins Univ, Sch Med, Ctr TB Res, Baltimore, MD USA.
Johns Hopkins Univ, Sch Med, Ctr TB Res, Baltimore, MD USA.
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
KwaZulu Natal Res Inst TB & HIV K RITH, Durban, South Africa.
Show others and affiliations
2015 (English)In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 235, no 3, 431-444 p.Article in journal (Refereed) Published
Abstract [en]

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 (>10(7) CFU/g) far greater than those found in matched granulomatous tissue (10(5) 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 (R(2) =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%).

Place, publisher, year, edition, pages
2015. Vol. 235, no 3, 431-444 p.
Keyword [en]
tuberculosis, matrix metalloproteinase, computed tomography, cavity
National Category
Microbiology in the medical area
URN: urn:nbn:se:umu:diva-93713DOI: 10.1002/path.4432ISI: 000347709000006PubMedID: 25186281OAI: diva2:750902
Available from: 2014-09-30 Created: 2014-09-30 Last updated: 2015-02-19Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Larsson, Christer
By organisation
Department of Molecular Biology (Faculty of Science and Technology)
In the same journal
Journal of Pathology
Microbiology in the medical area

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 54 hits
ReferencesLink to record
Permanent link

Direct link