title: The Extracellular Matrix Regulates Granuloma Necrosis in Tuberculosis.
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.
authors: Infectious Diseases and Immunity Section, Division of Infectious Diseases.
authors: Basim
authors: B
authors: Al Shammari
authors: Department of Medicine, Columbia University, New York, New York.
authors: Takayuki
authors: T
authors: Shiomi
authors: NIHR Respiratory Biomedical Research Unit, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine.
authors: Liku
authors: L
authors: Tezera
authors: NIHR Respiratory Biomedical Research Unit, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine.
authors: Magdalena K
authors: MK
authors: Bielecka
authors: BioPhysics Group, Department of Mechanical Engineering Institute of Biomedical Engineering Centre for Stem Cells and Regenerative Medicine, University College London.
authors: Victoria
authors: V
authors: Workman
authors: Infectious Diseases and Immunity Section, Division of Infectious Diseases.
authors: Tarangini
authors: T
authors: Sathyamoorthy
authors: Histopathology Department, Centre for Pathology, Division of Experimental Medicine.
authors: Francesco
authors: F
authors: Mauri
authors: BioPhysics Group, Department of Mechanical Engineering Institute of Biomedical Engineering Centre for Stem Cells and Regenerative Medicine, University College London.
authors: Suwan N
authors: SN
authors: Jayasinghe
authors: MRC Centre for Molecular Bacteriology and Infection, Department of Medicine, Imperial College London.
authors: Brian D
authors: BD
authors: Robertson
authors: Department of Medicine, Columbia University, New York, New York.
authors: Jeanine
authors: J
authors: D'Armiento
authors: Infectious Diseases and Immunity Section, Division of Infectious Diseases.
authors: Jon S
authors: JS
authors: Friedland
authors: Infectious 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.
authors: Paul T
authors: PT
authors: Elkington
mesh_terms: D000818:Animals; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000737:chemistry* / Q000378:metabolism*; D006099:Granuloma / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology*; D054884:Host-Pathogen Interactions; D006801:Humans; D008168:Lung / Q000737:chemistry / Q000473:pathology; D008175:Lung Neoplasms / Q000473:pathology; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009336:Necrosis / Q000378:metabolism / Q000473:pathology; D014376:Tuberculosis / Q000378:metabolism* / Q000473:pathology*
chemical_list: D003094:Collagen; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1
keywords: extracellular matrix; immunopathology; matrix metalloprotease; tuberculosis