The University of Southampton
University of Southampton Institutional Repository

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

Mycobacterium tuberculosis dysregulates MMP/TIMP balance to drive rapid cavitation and unrestrained bacterial proliferation.
Mycobacterium tuberculosis dysregulates MMP/TIMP balance to drive rapid cavitation and unrestrained bacterial proliferation.
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%).
431-444
Kubler, A.
4ffda2c6-0a9a-4356-b4d0-1066b6297147
Luna, B.
90970267-4cff-4558-9717-e31c4ea6f298
Larsson, C.
68c26533-ae1c-4258-bc79-ed0614a2f9e1
Ammerman, N.C.
fd64ece2-5366-4e44-923a-9f272485f698
Andrade, B.B.
e8a0a8cc-d98a-4f6d-9c02-9d5040a267f5
Orandle, M.
6f6d9a8c-ed9f-4c4e-83c9-b2f999f0d3d6
Bock, K.W.
46eaf103-29e4-4f8f-acf4-fe77e463aa5a
Xu, Z.
8bc2530e-2e30-431e-a219-98583ccb55e8
Bagci, U.
fc7205aa-f4d8-447f-942f-3a3b01a59fdf
Mulura, D.J.
ff3d295a-46a8-4099-b8e8-d6935221c845
Marshall, J.
6592d20b-7322-46ca-a8b2-27bb7b986fae
Burns, J.
ec8dca88-9dec-4780-a0d2-80ea1d16c7c3
Winglee, K.
fb74fef3-9165-49b2-b093-eac5bcf3ad3c
Ahidjo, B.A.
c0209709-531c-4778-be43-98a196af8e50
Cheung, L.S.
a3728136-8485-4f95-b52f-110618f5b8c1
Klunk, M.
a7122ebc-1f53-4b7a-b612-04c0ffdc34e8
Jain, S.K.
90722858-e055-436c-bf39-8f61b096ed27
Kumar, N.P.
180d6331-9918-48f2-a95d-e3ad659642e3
Babu, S.
666c5339-345d-4bf1-b0f5-a0a04385b038
Sher, A.
c148fa25-f000-48bd-845b-eae9af0a3979
Friedland, J.S.
e64a7af8-b969-4426-82e6-5ebe819799c9
Elkington, P.T.
60828c7c-3d32-47c9-9fcc-6c4c54c35a15
Bishai, W.R.
adcbabf1-0ec4-408e-b538-0998da585ce2
Kubler, A.
4ffda2c6-0a9a-4356-b4d0-1066b6297147
Luna, B.
90970267-4cff-4558-9717-e31c4ea6f298
Larsson, C.
68c26533-ae1c-4258-bc79-ed0614a2f9e1
Ammerman, N.C.
fd64ece2-5366-4e44-923a-9f272485f698
Andrade, B.B.
e8a0a8cc-d98a-4f6d-9c02-9d5040a267f5
Orandle, M.
6f6d9a8c-ed9f-4c4e-83c9-b2f999f0d3d6
Bock, K.W.
46eaf103-29e4-4f8f-acf4-fe77e463aa5a
Xu, Z.
8bc2530e-2e30-431e-a219-98583ccb55e8
Bagci, U.
fc7205aa-f4d8-447f-942f-3a3b01a59fdf
Mulura, D.J.
ff3d295a-46a8-4099-b8e8-d6935221c845
Marshall, J.
6592d20b-7322-46ca-a8b2-27bb7b986fae
Burns, J.
ec8dca88-9dec-4780-a0d2-80ea1d16c7c3
Winglee, K.
fb74fef3-9165-49b2-b093-eac5bcf3ad3c
Ahidjo, B.A.
c0209709-531c-4778-be43-98a196af8e50
Cheung, L.S.
a3728136-8485-4f95-b52f-110618f5b8c1
Klunk, M.
a7122ebc-1f53-4b7a-b612-04c0ffdc34e8
Jain, S.K.
90722858-e055-436c-bf39-8f61b096ed27
Kumar, N.P.
180d6331-9918-48f2-a95d-e3ad659642e3
Babu, S.
666c5339-345d-4bf1-b0f5-a0a04385b038
Sher, A.
c148fa25-f000-48bd-845b-eae9af0a3979
Friedland, J.S.
e64a7af8-b969-4426-82e6-5ebe819799c9
Elkington, P.T.
60828c7c-3d32-47c9-9fcc-6c4c54c35a15
Bishai, W.R.
adcbabf1-0ec4-408e-b538-0998da585ce2

Kubler, A., Luna, B., Larsson, C., Ammerman, N.C., Andrade, B.B., Orandle, M., Bock, K.W., Xu, Z., Bagci, U., Mulura, D.J., Marshall, J., Burns, J., Winglee, K., Ahidjo, B.A., Cheung, L.S., Klunk, M., Jain, S.K., Kumar, N.P., Babu, S., Sher, A., Friedland, J.S., Elkington, P.T. and Bishai, W.R. (2015) Mycobacterium tuberculosis dysregulates MMP/TIMP balance to drive rapid cavitation and unrestrained bacterial proliferation. The Journal of Pathology, 235, 431-444. (doi:10.1002/path.4432).

Record type: Article

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%).

Full text not available from this repository.

More information

Published date: 2015
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 368721
URI: https://eprints.soton.ac.uk/id/eprint/368721
PURE UUID: 5ff84369-2513-414c-aba7-fc6cbd2df248
ORCID for P.T. Elkington: ORCID iD orcid.org/0000-0003-0390-0613

Catalogue record

Date deposited: 09 Sep 2014 13:41
Last modified: 06 Jun 2018 12:28

Export record

Altmetrics

Contributors

Author: A. Kubler
Author: B. Luna
Author: C. Larsson
Author: N.C. Ammerman
Author: B.B. Andrade
Author: M. Orandle
Author: K.W. Bock
Author: Z. Xu
Author: U. Bagci
Author: D.J. Mulura
Author: J. Marshall
Author: J. Burns
Author: K. Winglee
Author: B.A. Ahidjo
Author: L.S. Cheung
Author: M. Klunk
Author: S.K. Jain
Author: N.P. Kumar
Author: S. Babu
Author: A. Sher
Author: J.S. Friedland
Author: P.T. Elkington ORCID iD
Author: W.R. Bishai

University divisions

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of https://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×