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Identification of a matrix-degrading phenotype in human tuberculosis in vitro and in vivo
N M Price1, J Farrar, T T Tran
1Department of Infectious Diseases, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom.
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.
Insights
Tuberculous meningitis involves brain damage from Mycobacterium tuberculosis. Monocytes release matrix metalloproteinase-9 (MMP-9), contributing to this injury by degrading tissue, with higher levels seen in severe cases.
Area of Science:
- Immunology
- Neuroscience
- Infectious Diseases
Background:
- Tuberculous meningitis (TBM) causes significant cerebral tissue destruction.
- Monocytes play a key role in the immune response to Mycobacterium tuberculosis.
- Matrix metalloproteinase-9 (MMP-9) secreted by monocytes aids leukocyte migration but can cause brain injury.
Purpose of the Study:
- To investigate the role of MMP-9 and its inhibitor TIMP-1 in TBM pathogenesis.
- To determine if MMP-9 secretion by monocytes is altered during M. tuberculosis infection.
- To correlate MMP-9 levels in cerebrospinal fluid (CSF) with clinical outcomes in TBM patients.
Main Methods:
- In vitro study using human monocytic THP-1 cells infected with M. tuberculosis.
- Measurement of MMP-9 and TIMP-1 mRNA and protein levels.
- In vivo analysis of MMP-9 and TIMP-1 concentrations in CSF from patients with TBM, bacterial meningitis, and viral meningitis.
Main Results:
- M. tuberculosis infection induced a dose-dependent increase in MMP-9 secretion by THP-1 cells.
- MMP-9 levels per leukocyte were significantly higher in CSF of TBM patients compared to bacterial or viral meningitis.
- Elevated MMP-9 levels in CSF correlated with fatal outcomes and signs of cerebral tissue damage in TBM patients.
Conclusions:
- M. tuberculosis-infected monocytes exhibit a matrix-degrading phenotype characterized by increased MMP-9 activity.
- This MMP-9 activity is relatively unrestricted by TIMP-1 in the TBM context, both in vitro and in vivo.
- The observed MMP-9 phenotype is functionally significant and linked to cerebral injury in tuberculous meningitis.