Elevated Levels of MMP‐9 and TIMP‐1 in the Cerebrospinal Fluid of Children with Echovirus Type 30 and Mumps Meningitis

Abstract

Matrix metalloproteinases are involved in leucocyte invasion into the central nervous system (CNS) during meningitis. The aim of the study was to determine whether there are differences in the expression patterns of matrix metalloproteinase‐9 (MMP‐9) and the tissue inhibitor of metalloproteinase‐1 (TIMP‐1) in the cerebrospinal fluid (CSF) of patients with meningitis caused by one of two known distinct viral agents. Concentrations were measured by using an enzyme‐linked immunosorbent assay (ELISA) in 16 children with mumps meningitis, in 25 children with echovirus type 30 meningitis and in a control group of 23 children without any CNS infection. Increased levels of MMP‐9 were found in children with mumps (median 0.48 ng/ml; P < 0.001) and enteroviral meningitis (median 2.76 ng/ml; P < 0.001) compared with that in controls (median: 0.01 ng/ml). Concentrations of TIMP‐1 greatly exceeded concentrations of MMP‐9 and were elevated in children with mumps (median: 56 ng/ml) and echovirus type 30 meningitis (median: 55 ng/ml) compared to controls (median: 17 ng/ml). No significant differences in MMP‐9 or TIMP‐1 levels were detected between the two meningitis groups. The MMP‐9/TIMP‐1 ratio was greater in children with echovirus type 30 than in those with mumps meningitis. There was no correlation between MMP‐9 levels and total CSF cell count. MMP‐9 correlated with CSF absolute neutrophil count in children with echovirus type 30 meningitis (r = 0.431; P < 0.05). The concentration of MMP‐9 is higher in children with viral meningitis, possibly because of infiltrating polymorphonuclear cells present in the initial phase of the disease.

Expression of matrix metalloproteinases and their tissue inhibitors in the serum and cerebrospinal fluid of patients with meningitis

“…Increased expression of MMP-9 and TIMP-1 in CSF of bacterial meningitis, viral meningoencephalitis and eosinophilic meningitis has also been reported by several groups [8,9,20,23]. The finding that concentrations of TIMP-1 were ten to hundreds-fold higher than MMP-9 in patients with viral [23] and eosinophilic meningitis [9] and in our patients, suggests that MMP-9 is bound to TIMP-1 [24]. In a mouse brain experimental autoimmune encephalomyelitis (EAE) model, Pagenstecher et al [25] showed that upregulation of MMP-9 was associated with marked enhancement of TIMP-1 expression.…”

“…A significant increase in CNS concentrations of TIMP‐1 has been observed in infectious meningitis [8,9]. Increased expression of MMP‐9 and TIMP‐1 in CSF of bacterial meningitis, viral meningoencephalitis and eosinophilic meningitis has also been reported by several groups [8,9,20,23]. The finding that concentrations of TIMP‐1 were ten to hundreds‐fold higher than MMP‐9 in patients with viral [23] and eosinophilic meningitis [9] and in our patients, suggests that MMP‐9 is bound to TIMP‐1 [24].…”

Type-I interferons induce lung protease responses following respiratory syncytial virus infection via RIG-I-like receptors

“…Indeed, the induction of MMP-9 by Influenza A virus was associated with severe lung pathology in mice 35 and the regulation of neutrophil migration 36 . Also, MMP-9 is higher in children with mumps meningitis 37 . Sendai virus increases MMP-9 activity to drive pneumonia progression by enhancing virus multiplication and aids in the destruction of lung matrix in rats 34 .…”

Dexamethasone, Cerebrospinal Fluid Matrix Metalloproteinase Concentrations and Clinical Outcomes in Tuberculous Meningitis

“…Other studies have reported strong correlations between MMP-9 and neutrophils in viral meningitis and with total white cells in TBM [26], [27]. Neutrophils release large amounts of preformed MMP-9 in response to many inflammatory stimuli, which may explain the lack of correlation observed between CSF MMP-9 and the pro-inflammatory cytokines measured [28].…”