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

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 results 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 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 (R2=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%).

Tuberculosis as a three-act play: A new paradigm for the pathogenesis of pulmonary tuberculosis

“…Cavities may contain many neutrophils. Recent publications report that neutrophils and proteases contribute to the softening and fragmentation that leads to cavitation 7, 62, 74, 75 . While this may be true, the data are not convincing because investigators have not been able to study developing post primary TB.…”

Hypoxia and tissue destruction in pulmonary TB

“…15 In presensitised rabbits, MMP-1 has been shown to have a causal role in pulmonary cavitation. 27 Specifically, the development of cavities within areas of dense consolidation has been associated with MMP-1/ TIMP imbalance and high intracavitary bacterial burden. In human TB granulomas, MMP-1 expression is upregulated 606-fold compared with uninfected lung.…”

Pathology and immune reactivity: understanding multidimensionality in pulmonary tuberculosis

“…The well-suited model for cavitation, the rabbit, has been reinvestigated [177], and provides compelling evidence that matrix-degrading enzymes are essential for progression of dense consolidated lesions-which are distinct from granulomas-to cavitation [177]. Studies in guinea pigs [178] and mice [179][180][181] further indicate that breakdown of lung collagen is essential for necrosis, which likely precedes cavitation.…”

“…Paucity of lymphocytes likely explains massive bacillary replication at the cavity wall [60]. However, in animal models, strength of the DTH correlates with cavity formation [59,189] and with the protease imbalance [177]. Adoptive cell transfer studies in the TDM-induced granuloma model have indicated a major role of the CD4 + T lymphocytes in induction of tissue injury [190].…”

“…Abundance of this collagenase correlates with extent of tissue damage [172]. Recent investigations have further elaborated on kinetics of cavity formation and revealed that host protease imbalances promote cavitation [177]. CT scans, histology, and zymography collectively show that thresholds of MMP-1 and tissue inhibitors of matrix proteases (TIMP) affect progression of consolidated foci towards cavities in a fast remodeling process.…”