The extracellular matrix regulates granuloma necrosis in tuberculosis

Abstract

A central tenet of tuberculosis (TB) pathogenesis is that caseous necrosis leads to extracellular matrix destruction and bacterial transmission. We reconsider the underlying mechanism of TB pathology and demonstrate that collagen destruction may be a critical initial event, causing caseous necrosis as opposed to resulting from it. In human TB 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 TB. Collagen destruction is the principal pathological difference to wild type mice, whereas the release of pro-inflammatory 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 TB granuloma formation utilising bioelectrospray technology. Collagen improved survival of Mycobacterium tuberculosis-infected cells analyzed by LDH release, propidium iodide staining and total viable cells. Taken together, these findings suggest that collagen destruction is an initial event in TB 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.

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Identifiers

ORCID for L. Tezera: orcid.org/0000-0002-7898-6709

ORCID for P.T. Elkington: orcid.org/0000-0003-0390-0613

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