ArticleThe Journal of pathology2015
Mycobacterium tuberculosis dysregulates MMP/TIMP balance to drive rapid cavitation and unrestrained bacterial proliferation.
Article in The Journal of pathology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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Who cites it
62 citing papers in PubMed, 102 citations in OpenAlex.
- Doxycycline host-directed therapy in human pulmonary tuberculosis.The Journal of clinical investigation · 2021Trial
- Glucose driven bacterial persistence in extensively drug-resistant tuberculosis with diabetes.Frontiers in public health · 2026Article
- Serum cytokine analysis in cavitary and non-cavitary pulmonary Mycobacterium avium complex disease: a cross-sectional study.BMC infectious diseases · 2025Article
- Experimental dissection of tuberculosis protective immunity: a human perspective.Frontiers in cellular and infection microbiology · 2025Review
- Leveraging insights from cancer to improve tuberculosis therapy.Trends in molecular medicine · 2025Article
- Pathogenesis of Post-Tuberculosis Lung Disease: Defining Knowledge Gaps and Research Priorities at the Second International Post-Tuberculosis Symposium.American journal of respiratory and critical care medicine · 2024Review
- Article
- Normalizing granuloma vasculature and matrix improves drug delivery and reduces bacterial burden in tuberculosis-infected rabbits.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Review
- An acidic microenvironment in Tuberculosis increases extracellular matrix degradation by regulating macrophage inflammatory responses.PLoS pathogens · 2023Article
- Review
- Association between Serum Cys C and PTB Cavitation.Disease markers · 2023Article
- Doxycycline as a Potential MMP-1 Inhibitor for the Treatment of Spondylitis Tuberculosis: A Study in Rabbit Model.BioMed research international · 2023Article
- Animal models for COVID-19 and tuberculosis.Frontiers in immunology · 2023Review
- Article
- Response to Hypoxia and the Ensuing Dysregulation of Inflammation ImpactsAmerican journal of respiratory and critical care medicine · 2022Article
- Mycobacterium avium-intracellulare complex promote release of pro-inflammatory enzymes matrix metalloproteinases by inducing neutrophil extracellular trap formation.Scientific reports · 2022Article
- Host-directed therapies in pulmonary tuberculosis: Updates on anti-inflammatory drugs.Frontiers in medicine · 2022Review
- Remodeling the matrix: doxycycline modulates tuberculosis immunopathology.The Journal of clinical investigation · 2021Article
- Sensing of mycobacterial arabinogalactan by galectin-9 exacerbates mycobacterial infection.EMBO reports · 2021Article
2 more citing papers are in PubMed but not listed here.
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Authors and funding
23 authors at 8 institutions in 4 countries.
Funding
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 (>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%).
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.