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J Infect Dis. 2015 Aug 1;212(3):463-73. doi: 10.1093/infdis/jiv076. Epub 2015 Feb 12.

The Extracellular Matrix Regulates Granuloma Necrosis in Tuberculosis.

Author information

  • 1Infectious Diseases and Immunity Section, Division of Infectious Diseases.
  • 2Department of Medicine, Columbia University, New York, New York.
  • 3NIHR Respiratory Biomedical Research Unit, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine.
  • 4BioPhysics Group, Department of Mechanical Engineering Institute of Biomedical Engineering Centre for Stem Cells and Regenerative Medicine, University College London.
  • 5Histopathology Department, Centre for Pathology, Division of Experimental Medicine.
  • 6MRC Centre for Molecular Bacteriology and Infection, Department of Medicine, Imperial College London.
  • 7Infectious Diseases and Immunity Section, Division of Infectious Diseases NIHR Respiratory Biomedical Research Unit, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine Institute for Life Sciences, University of Southampton, United Kingdom.

Abstract

A central tenet of tuberculosis pathogenesis is that caseous necrosis leads to extracellular matrix destruction and bacterial transmission. We reconsider the underlying mechanism of tuberculosis pathology and demonstrate that collagen destruction may be a critical initial event, causing caseous necrosis as opposed to resulting from it. In human tuberculosis granulomas, regions of extracellular matrix destruction map to areas of caseous necrosis. In mice, transgenic expression of human matrix metalloproteinase 1 causes caseous necrosis, the pathological hallmark of human tuberculosis. Collagen destruction is the principal pathological difference between humanised mice and wild-type mice with tuberculosis, whereas the release of proinflammatory cytokines does not differ, demonstrating that collagen breakdown may lead to cell death and caseation. To investigate this hypothesis, we developed a 3-dimensional cell culture model of tuberculosis granuloma formation, using bioelectrospray technology. Collagen improved survival of Mycobacterium tuberculosis-infected cells analyzed on the basis of a lactate dehydrogenase release assay, propidium iodide staining, and measurement of the total number of viable cells. Taken together, these findings suggest that collagen destruction is an initial event in tuberculosis immunopathology, leading to caseous necrosis and compromising the immune response, revealing a previously unappreciated role for the extracellular matrix in regulating the host-pathogen interaction.

© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

KEYWORDS:

extracellular matrix; immunopathology; matrix metalloprotease; tuberculosis

PMID:
25676469
[PubMed - indexed for MEDLINE]
PMCID:
PMC4539912
[Available on 2016-08-01]
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