Identification of a Matrix-Degrading Phenotype in Human Tuberculosis In Vitro and In Vivo

Abstract

Tuberculous meningitis is characterized by cerebral tissue destruction. Monocytes, pivotal in immune responses to Mycobacterium tuberculosis, secrete matrix metalloproteinase-9 (MMP-9), which facilitates leukocyte migration across the blood-brain barrier, but may cause cerebral injury. In vitro, human monocytic (THP-1) cells infected by live, virulent M. tuberculosis secreted MMP-9 in a dose-dependent manner. At 24 h, MMP-9 concentrations increased 10-fold to 239 ± 75 ng/ml (p = 0.001 vs controls). MMP-9 mRNA became detectable at 24–48 h. In contrast, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) gene expression and secretion were similar to constitutive levels from controls at 24 h and increased just 5-fold by 48 h. In vivo investigation revealed MMP-9 concentration per leukocyte in cerebrospinal fluid (CSF) from tuberculous meningitis patients (n = 23; median (range), 3.19 (0.19–31.00) ng/ml/cell) to be higher than that in bacterial (n = 12; 0.23 (0.01–18.37) ng/ml/cell) or viral meningitis (n = 20; 0.20 (0.04–31.00) ng/ml/cell; p < 0.01). TIMP-1, which was constitutively secreted into CSF, was not elevated in tuberculous compared with bacterial meningitis or controls. Thus, a phenotype in which MMP-9 activity is relatively unrestricted by TIMP-1 developed both in vitro and in vivo. This is functionally significant, since MMP-9 concentrations per CSF leukocyte (but not TIMP-1 concentrations) were elevated in fatal tuberculous meningitis and in patients with signs of cerebral tissue damage (unconsciousness, confusion, or neurological deficit; p < 0.05). However, MMP-9 activity was unrelated to the severity of systemic illness. In summary, M. tuberculosis-infected monocytic cells develop a matrix-degrading phenotype, which was observed in vivo and relates to clinical signs reflecting cerebral injury in tuberculous meningitis.

Monocyte-Astrocyte Networks Regulate Matrix Metalloproteinase Gene Expression and Secretion in Central Nervous System Tuberculosis In Vitro and In Vivo

“…However, it does appear in a range of inflammatory diseases of the CNS where it is thought to contribute to damage of the parenchymal tissues and the BBB (10,34). In tuberculous meningitis patients, CSF MMP-9 concentrations are significantly associated with mortality and local tissue damage (12). Astrocytes did not secrete MMP-9 after direct infection with M. tuberculosis.…”

“…MMP-9 concentrations are increased in cerebrospinal fluid (CSF) from patients with CNS-TB (3,11) and we showed that MMP-9 concentrations are associated with neurological complications and death (12). The effect of active tuberculous on CSF TIMP-1 concentrations is variable and may be increased or remain unchanged (11,12).…”

“…The effect of active tuberculous on CSF TIMP-1 concentrations is variable and may be increased or remain unchanged (11,12). In our previous study, TIMP-1 CSF concentrations were not related to clinical signs of disease severity (12). The NF-B-signaling pathway is implicated in differential regulation of TIMP-1 and MMP-9 (13) and is activated during host responses to M. tuberculosis in other tissues (14).…”

Monocyte‐dependent oncostatin M and TNF‐α synergize to stimulate unopposed matrix metalloproteinase‐1/3 secretion from human lung fibroblasts in tuberculosis

“…The pathological response to Mycobacterium tuberculosis (Mtb) infection is characterised by extensive tissue breakdown including caseous necrosis, and later fibrosis. Tissue destruction in TB requires degradation of matrix proteins including collagen and elastin, and several studies have implicated matrix metalloproteinases (MMP) in pathogenesis [1][2][3]. MMP are a group of 23 related zinc-dependent enzymes that together are capable of degrading all components of the extracellular matrix (ECM) [4].…”

MMPs are regulatory enzymes in pathways of inflammatory disorders, tissue injury, malignancies and remodelling of the lung

“…Fibrillar collagens, which are highly resistant to enzymatic cleavage, are important constituents of the pulmonary extracellular matrix. However, collectively, MMPs are able to degrade all components of the extracellular matrix, resulting in cavities [4], and about a decade ago it was recognised that lung extracellular matrix destruction by MMPs was essential to tuberculosis [5]. The destruction of extracellular matrix by MMPs allows mycobacteria to spread from the interstitium to the airways, and results in cavities with an immunodeficient milieu in which mycobacteria can proliferate as a consequence of a missing protective immune response.…”