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.

Mathematical Model of Oxygen Transport in Tuberculosis Granulomas

“…We propose, based on our recent experimental observations, 11 that in TB, as in solid cancerous tumors, these conditions are largely the result of an abnormal granuloma-associated vasculature that results in hypoxia, especially in avascular regions. While other factors have been identified as potential causes of necrosis, such as breakdown of extracellular matrix 1 and immune/inflammatory processes 33 including cell death, 30 this work definitively identifies oxygen as a major player in its emergence. While further studies are required to illuminate all of the physiological abnormalities and molecular mechanisms that may contribute to hypoxia and necrosis, the results of this simple model, in agreement with experimental data, quantitatively support the hypothesis that low oxygen supply is a key contributor of necrosis in TB granulomas.…”

Dissection of the host-pathogen interaction in human tuberculosis using a bioengineered 3-dimensional model

“…A specific advantage of 3-D cell culture incorporating extracellular matrix is that cellular survival is greatly prolonged (Buchheit et al, 2012; Mueller-Klieser, 1997). Furthermore, inflammatory signalling in TB granulomas is spatially organised (Marakalala et al, 2016), with specific microenvironments (Mattila et al, 2013), and the extracellular matrix regulates cell survival in TB (Al Shammari et al, 2015), indicating that an optimal system to study human disease will need to be 3-D with extracellular matrix.…”

Permutations of time and place in tuberculosis

“…However, alternative hypotheses have been suggested, such as differential lymphatic drainage 20 or reduced blood flow 15 . Enzymes such as the collagenase matrix metalloproteinase-1 must be the final effectors of extracellular matrix destruction that leads to cavity formation 21, 22 , and collagen breakdown favours Mtb in the host-pathogen interaction 23 . Therefore, alternative hypotheses for the apical localization would include increased susceptibility to extracellular matrix breakdown, due to reduced availability of plasma antiproteases and the increased susceptibility of collagen under tension to enzymatic cleavage 24 , or the modulation of cellular biology by tissue stiffness 25 .…”