title: 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 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%).
authors.affiliation: Infectious Diseases and Immunity, Imperial College London, UK; Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: André
authors.initials: A
authors.lastname: Kübler
authors.forename: Brian
authors.initials: B
authors.lastname: Luna
authors.forename: Christer
authors.initials: C
authors.lastname: Larsson
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Ammerman
authors.forename: Bruno B
authors.initials: BB
authors.lastname: Andrade
authors.forename: Marlene
authors.initials: M
authors.lastname: Orandle
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Bock
authors.forename: Ziyue
authors.initials: Z
authors.lastname: Xu
authors.forename: Ulas
authors.initials: U
authors.lastname: Bagci
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Mollura
authors.forename: John
authors.initials: J
authors.lastname: Marshall
authors.forename: Jay
authors.initials: J
authors.lastname: Burns
authors.forename: Kathryn
authors.initials: K
authors.lastname: Winglee
authors.forename: Bintou Ahmadou
authors.initials: BA
authors.lastname: Ahidjo
authors.forename: Laurene S
authors.initials: LS
authors.lastname: Cheung
authors.forename: Mariah
authors.initials: M
authors.lastname: Klunk
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Jain
authors.forename: Nathella Pavan
authors.initials: NP
authors.lastname: Kumar
authors.forename: Subash
authors.initials: S
authors.lastname: Babu
authors.forename: Alan
authors.initials: A
authors.lastname: Sher
authors.forename: Jon S
authors.initials: JS
authors.lastname: Friedland
authors.forename: Paul T G
authors.initials: PT
authors.lastname: Elkington
authors.forename: William R
authors.initials: WR
authors.lastname: Bishai
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006706:Homeostasis / Q000502:physiology; D007091:Image Processing, Computer-Assisted; D008168:Lung / Q000000981:diagnostic imaging / Q000382:microbiology* / Q000473:pathology*; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D045726:Metalloproteases / Q000378:metabolism*; D009169:Mycobacterium tuberculosis / Q000254:growth & development* / Q000502:physiology*; D011817:Rabbits; D012882:Skin Tests; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism*; D014057:Tomography, X-Ray Computed; D014376:Tuberculosis / Q000378:metabolism / Q000473:pathology*
chemical_list: D019717:Tissue Inhibitor of Metalloproteinase-3; D019714:Tissue Inhibitor of Metalloproteinases; D045726:Metalloproteases; D020781:Matrix Metalloproteinase 1
keywords: cavity; computed tomography; matrix metalloproteinase; tuberculosis