Role for Matrix Metalloproteinase 9 in Granuloma Formation during PulmonaryMycobacterium tuberculosisInfection

Abstract

Recent studies have shown that matrix metalloproteinases (MMPs) are induced by Mycobacterium tuberculosis during pulmonary infection. Here, expression of MMP-9 during pulmonary M. tuberculosis infection was characterized to determine whether its production correlated with disease resistance in vivo and to determine what role, if any, MMP-9 might have in granuloma formation. Following aerosol infection with M. tuberculosis, dissemination of bacilli occurred earlier in the C57BL/6 resistant mouse strain than in the susceptible CBA/J strain, as was evident from an increased number of bacteria in the blood, spleen, and liver at day 14 after infection. In addition, early dissemination of the bacilli was associated with early induction of protective immunity as assessed from gamma interferon levels. Nonspecific blocking of MMPs in C57BL/6 mice early during infection reduced hematogenous spread of the bacilli, suggesting that MMPs indeed play a role in facilitating dissemination, likely via extracellular matrix degradation. The concentration of active MMP-9, specifically, was greater in the lungs of C57BL/6 mice than in those of the CBA/J mice at day 28, thereby suggesting that MMP-9 is not one of the MMPs directly involved in promoting early dissemination of M. tuberculosis. Instead, however, histological lung sections and flow cytometric analysis of lung cells from MMP-9-knockout mice showed that MMP-9 is involved in macrophage recruitment and granuloma development. These combined data support the idea that early MMP activity is an essential component of resistance to pulmonary mycobacterial infection and that MMP-9, specifically, is required for recruitment of macrophages and tissue remodeling to allow for the formation of tight, well-organized granulomas.

Immunity and Immunopathology in the Tuberculous Granuloma

“…Among tuberculous meningitis patients, increased MMP9 levels in the cerebrospinal fluid are associated with worse outcomes (Price et al 2003). In a mouse model of M. tuberculosis aerosol infection, MMP9 knockout mice recruited fewer macrophages to the lung and formed smaller granulomas, features that were associated with reduced lung bacterial loads as early as 2 wk postinfection and continuing through the 120-d assay period (Taylor et al 2006). These data implicate MMP9 and granuloma formation in pathogenesis similar to the zebrafish and human data.…”

1α,25‐dihydroxyvitamin D3 inhibits matrix metalloproteinases induced by Mycobacterium tuberculosis infection

“…37 This dichotomy is illustrated in a study reporting that MMP-9 knockout mice infected with M. tuberculosis exhibit impaired macrophage recruitment and granuloma development, while administration of a broad-range MMP inhibitor to wild-type mice exposed to M. tuberculosis infection reduces haematogenous spread of infection. 38 In humans, administration of vitamin D to patients with pulmonary TB has been reported to reduce both cavitation 39 and time to sputum smear conversion 40 suggesting that vitamin D supplementation may afford a net clinical benefit associated with enhanced resolution of pulmonary cavitation. Clinical studies of the effect of vitamin D supplementation on MMP regulation in TB patients are required, and are a current focus of our work.…”

Glycolytic and Non-glycolytic Functions of Mycobacterium tuberculosis Fructose-1,6-bisphosphate Aldolase, an Essential Enzyme Produced by Replicating and Non-replicating Bacilli

“…In the context of TB infection, a deregulation of plasmin-dependent pathways could have a major impact on the inflammatory response and induction of host metalloproteinases with consequences on granuloma formation (61), lung tissue destruction (62), and bacterial dissemination. Experiments using cellular models of infection and in vivo studies involving conditional fba-tb gene silencing in M. tuberculosis H37Rv (63) are in progress to directly test these hypotheses and assess the essential character of FBA-tb throughout the different stages of the infection.…”