Defining the role of matrix metalloproteinases in tb granuloma formation

Abstract

Tuberculosis (TB) remains a global health emergency and one third of the global population harbour latent infection. A central tenet of TB pathology is that caseation of TB granuloma leads to matrix degradation and pulmonary cavitation, resulting in Mtb transmission and disease progression. However, lung destruction must involve activity of MMPs which are emerging as key proteases contributing to lung tissue pathology in TB. MMP-1 is the dominant collagenase in human pulmonary TB, but mice do not express an orthologue of human MMP-1 in the lung. The precise relationship between the formation of caseous necrosis and lung matrix destruction has not been systematically examined, nor how the extracellular matrix (ECM) regulates the host-pathogen interaction. I investigated the effect of transgenic expression of human MMP-1 and -9 in the mouse on TB pathology and studied lung matrix integrity in human TB granulomas by ECM stains. In cell culture systems, I developed a standard in vitro granuloma model and then progressed to 3D and engineered models of TB granuloma and investigated the effect of modulating cell-matrix interaction by introducing matrix components. In the mouse model, transgenic expression of human MMP-1 caused collagen destruction and caseous necrosis, suggesting that the initial event in caseation is collagen breakdown. In human granulomas, ECM destruction and caseous necrosis co-localise, with loss of collagen fibres in areas of caseous necrosis. Consistent with the hypothesis that matrix degradation is a key initial event in TB pathogenesis, I demonstrated that in cell culture models collagen improves survival of Mtb-infected cells. I have re-considered the sequence of events underlying TB immunopathology and demonstrated that collagen destruction driven by MMP-1 is a critical initial event. This challenges current paradigms of disease pathology. These data demonstrate that the ECM regulates the host-pathogen interaction in TB.