Identification of a matrix-degrading phenotype in human tuberculosis in vitro and in vivo

Tuberculous meningitis is characterized by cerebral tissue destruction. Mon ocytes, pivotal in immune responses to Mycobacterium tuberculosis, secrete matrix metalloproteinase-9 (MMP-9), which facilitates leukocyte migration a cross the blood-brain barrier, but may cause cerebral injury. In vitro, hum an monocytic (THP-1) cells infected by live, virulent M, tuberculosis secre ted MMP-9 in a dose-dependent manner, At 24 h, MMP-9 concentrations increas ed 10-fold to 239 +/- 75 ng/ml (p = 0.001 vs controls). MMP-9 mRNA became d etectable at 24-48 h. In contrast, tissue inhibitor of matrix metalloprotei nase-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 inv estigation revealed MMP-9 concentration per leukocyte in cerebrospinal flui d (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 T IMP-1 developed both in vitro and in vivo. This is functionally significant , since MMP-9 concentrations per CSF leukocyte (but not TIMP-1 concentratio ns) were elevated in fatal tuberculous meningitis and in patients with sign s of cerebral tissue damage (unconsciousness, confusion, or neurological de ficit; p < 0.05), However, MMP-9 activity was unrelated to the severity of systemic illness, In summary, M. tuberculosis-infected monocytic cells deve lop a matrix-degrading phenotype, which was observed in vivo and relates to clinical signs reflecting cerebral injury in tuberculous meningitis.