Inhibition of Tissue Matrix Metalloproteinases Interferes with Mycobacterium tuberculosis-Induced Granuloma Formation and Reduces Bacterial Load in a Human Lung Tissue Model

Abstract

Granulomas are hallmarks of pulmonary tuberculosis (TB) and traditionally viewed as host-protective structures. However, recent evidence suggest that Mycobacterium tuberculosis (Mtb) uses its virulence factors to stimulate the formation of granuloma. In the present study, we investigated the contribution of matrix metalloproteinases (MMPs), host enzymes that cause degradation of the extracellular matrix, to granuloma formation and bacterial load in Mtb-infected tissue. To this end, we used our lung tissue model for TB, which is based on human lung-derived cells and primary human monocyte-derived macrophages. Global inhibition of MMPs in the Mtb-infected tissue model reduced both granuloma formation and bacterial load. The infection caused upregulation of a set of MMPs (MMP1, 3, 9, and 12), and this finding could be validated in lung biopsies from patients with non-cavitary TB. Data from this study indicate that MMP activation contributes to early TB granuloma formation, suggesting that host-directed, MMP-targeted intervention could be considered as adjunct therapy to TB treatment.

In Vitro Granuloma Models of Tuberculosis: Potential and Challenges

“…Further, matrix metalloproteinases (MMPs) secreted by host cells in infected tissue as a consequence of mycobacterial virulence factors can promote granuloma formation in zebrafish [2] and are implicated in human tuberculosis pathology [26,27]. These observations have been investigated and confirmed using the human in vitro lung tissue model, dissecting the set of MMPs induced by M. tuberculosis infection, and demonstrating that MMP inhibition reduces both granuloma pathology and bacterial load [28]. Furthermore, these findings are consistent with subsequent reports of the benefit of MMP inhibition in a mouse model of tuberculosis [29].…”

A complex interplay between the extracellular matrix and the innate immune response to microbial pathogens

“…reported up‐regulation of MMP‐1, MMP‐3, MMP‐9 and MMP‐12 in a human lung‐tissue model and in biopsies from patients with non‐cavitary tuberculosis. Global MMP inhibition via marimastat reduced granuloma formation and bacterial load …”

Macrophage functions in wound healing

“…These data indicate that macrophage subtype composition of the wound influences the outcome of extracellular matrix remodelling. In recent studies, Parasa et al () used newly developed experimental human lung tissue model containing human monocytes and differentiated macrophages to study how MMPs inhibition influences tuberculosis granuloma formation, which is similar to the granulation tissue formed during proliferative phase of wound healing. To inhibit MMP activity, they used a global MMP inhibitor, 200‐nM Marimastat (Merck Millipore).…”