Identification of a matrix-degrading phenotype in human tuberculosis in vitro and in vivo.
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.
Price
N M
NM
Department of Infectious Diseases, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom.
Farrar
J
J
Tran
T T
TT
Nguyen
T H
TH
Tran
T H
TH
Friedland
J S
JS
D000328:Adult; D002460:Cell Line; D004789:Enzyme Activation / Q000235:genetics; D005109:Extracellular Matrix / Q000201:enzymology* / Q000382:microbiology / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007958:Leukocyte Count; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D016920:Meningitis, Bacterial / Q000134:cerebrospinal fluid / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008587:Meningitis, Viral / Q000134:cerebrospinal fluid / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D009000:Monocytes / Q000201:enzymology / Q000378:metabolism / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000472:pathogenicity; D010641:Phenotype; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014390:Tuberculosis, Meningeal / Q000134:cerebrospinal fluid / Q000201:enzymology* / Q000382:microbiology / Q000473:pathology
D019715:Tissue Inhibitor of Metalloproteinase-1; D020780:Matrix Metalloproteinase 9