Title: role of matrix metalloproteinase −9 in progression of tuberculous meningitis: a pilot study in patients at different stages of the disease

Abstract

BackgroundTBM (Tuberculous meningitis) is severe form of tuberculosis causing death of one third of the affected individuals or leaving two-third of the survivors disabled. MMP-9 (Matrix metalloproteinase-9) is produced by the central nervous system in a variety of inflammatory conditions and has a role in the breakdown of extracellular matrix and blood–brain barrier.MethodsIn this study, the levels of MMP-9 and its inhibitor, TIMP-1 (tissue inhibitor of metalloproteinases-1), were screened using zymography and reverse zymography in cerebrospinal fluid and serum of tuberculous meningitis patients at different stages of the disease. Further, role of MMP-9 as therapeutic target was studied in C6 glioma cells infected with Mycobacterium tuberculosis H37Rv. Cells were treated with dexamethasone or SB-3CT (specific inhibitor of MMP-9) in combination with conventional antitubercular drugs.ResultsMMP-9 levels in patients were increased as the disease progressed to advanced stages. The infection led to increased MMP-9 levels in C6 glioma cells and specific inhibition of MMP-9 by SB-3CT augmented bacillary clearance when used along with antitubercular drugs.ConclusionMMP-9 plays a prominent role in progression of tuberculous meningitis from initial to advanced stages. Increased levels of MMP-9 during advancement of the disease leads to degeneration of nervous tissue and blood brain barrier disruption. Hence, MMP-9 can be considered as a therapeutic target for efficient management of TBM and can be explored to inhibit further progression of the disease if used at an early stage.

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

“…The involvement of these MMPs in granulomatous tissues had been shown separately in different models including mice (Ramos-Martinez et al, 2015 ; Ordonez et al, 2016 ), rabbits (Kubler et al, 2015 , 2016 ), fish (van der Sar et al, 2009 ; Volkman et al, 2010 ), and human tissues (Ong et al, 2015 ; Sathyamoorthy et al, 2015 ). Similar to our results, it has been shown that in human lung tissue biopsies of patients with TB, MMPs can be located in the macrophages surrounding the areas with caseous necrosis, (Elkington et al, 2005 ), at sites of tissue destruction (Green et al, 2010 ) and in cerebrospinal fluid during TB meningitis (Majeed et al, 2016 ). MMP9 is induced in epithelial cells surrounding growing granuloma, but its activity is dependent on the presence of macrophages (Elkington et al, 2007 ; Volkman et al, 2010 ).…”

MMPs and ADAMs in neurological infectious diseases and multiple sclerosis

“…Tuberculous meningitis (TBM), which arises rarely as an extrapulmonary form of tuberculosis, is associated with neurofunctional complications [146]. In patients with TBM, levels of MMP-2 and MMP-9 were found to be elevated, and high levels of MMP-9 were associated with late neurofunctional deficits [147,148]. Adjuvant dexamethasone during TBM was shown to reduce MMP-9 levels early in treatment and might represent one way by which dexamethasone reduces mortality in TBM [149,150].…”

Chronic Hypoxia-Induced Microvessel Proliferation and Basal Membrane Degradation in the Bone Marrow of Rats Regulated through the IL-6/JAK2/STAT3/MMP-9 Pathway

“…MMPs are a family of zinc-dependent endopeptidases with more than 20 different members [28,29]. MMP-9, a member of the MMP family, plays a crucial role in regulating angiogenesis and BM degradation under hypoxic conditions [30,31].…”