Chemokines and chemotaxis of leukocytes in infectious meningitis
Introduction
The major pathogens in acute community acquired bacterial meningitis include Streptococcus pneumoniae, Hemophilus influenzae and Neisseria meningitidis. The diagnosis is based on examination of CSF. The CSF white cell count is usually in the range of 1000–5000 μl−1 with a neutrophil predominance (Tunkel and Scheld, 1995). In contrast, monocytes and activated T cells account for CSF pleocytosis in viral meningitis, which is caused mainly by enteroviruses or paramyxoviruses (Schlitt et al., 1991). In viral meningitis, the number of cells is not more than several hundreds per μl neutrophils being found at the onset of the disease only. The disease caused by bacteria remains a serious clinical problem, mortality rates being still 20–30%. Leukocytes initiate and propagate brain injury by releasing toxic products. These include proteases, glutamate, reactive oxygen intermediates, NO, the latter molecules have been shown to be key mediators of the pathological changes in bacterial meningitis (for review see Pfister and Scheld, 1997). Brain injury results mainly from cerebrovascular involvement leading to cerebral ischemia, brain edema, hydrocephalus and increased intracranial pressure (Pfister et al., 1992). In contrast, viral meningitis is a relative benign disease with rare fatal outcome.
Section snippets
The concept of chemokines and matrix metalloproteinases to guide the recruitment of leukocytes into the CSF compartment
Bacterial meningitis can be initiated by nasopharyngeal colonization and invasion of bacteria, followed by CNS invasion. Part of the host response in infectious meningitis is the recruitment of leukocytes through the blood vessels into the meninges, the choroid plexus and the CSF compartment. Based on studies in other tissues, this process is thought to comprise four steps: rolling of leukocytes along the vessel walls, activation of integrins on the surface of the leukocytes, activation
Chemokines and their involvement in inflammation of the CNS
Chemokines constitute a large family of small inflammatory cytokines involved in the recruitment and activation of a wide variety of cell types (Oppenheim et al., 1991; Miller and Krangel, 1992; Oppenheim, 1993; Baggiolini et al., 1994, Baggiolini et al., 1997), (Table 1Table 2). The nomenclature of chemokines is based on the position of conserved cysteines within the amino acid sequence. The CXC subfamily consists of chemokines bearing four conserved cysteines, the two first being separate by
Production of MIP-1 and MIP-2 in meningeal infiltrates and the choroid plexus in experimental Listeria meningitis
A review of 493 episodes of bacterial meningitis in patients with 16 yr or older at a Boston hospital between 1962 and 1988 revealed Listeria monocytogeneses (LM) to be the causative agent in 8% of the cases. In patients aged 60 yr or more the corresponding figure was 15% (Calder, 1997). In the CSF, Listeria are eliminated intracellularly by IFNγ and TNFα activated monocytes (Frei et al., 1993). To investigate the site of production of chemokines in bacterial meningitis and their involvement in
In humans the neutrophilic response in the CSF correlates with expression of IL-8 in viral but not in bacterial meningitis
We and other groups have analyzed the chemokine levels of the two CXC chemokines IL-8 and GROα in the CSF of patients with infectious meningitis. These two chemokines exert strong chemotactic activity on neutrophils. In agreement with other studies we could detect elevated IL-8 levels in the CSF of patients with meningitis compared to the CSF of patients with inflammatory diseases not involving the CNS (Fig. 1, Table 3), (Van Meir et al., 1992; Lopez Cortes et al., 1995; Ostergaard et al., 1996
The CSF chemotactic activity for PBMC is mainly due to MCP-1
Monocytes and activated T cells predominate the second phase of viral meningitis. In bacterial meningitis caused by N. meningitidis, S. pneumoniae and H. influenzae, mononuclear cells are not prominent but may increase with time of disease (Schlitt et al., 1991). As signs for activation of the T cells in viral meningitis the expression of surface DR antigens and of transcripts for IFNγ and perforin were used and found to be highly increased in T cells derived from CSF taken in the acute phase
Concentrated action of CSF derived MCP-1 and IP-10 on chemotaxis of activated T cells
The chemotactic signals acting on activated T cells comprise IP-10, MCP-1, RANTES, MIP-1α, MIP-1β, IL-15 and IL-16. Among the chemokines acting on activated T-cells not only MCP-1 but also IP-10 was detected in the CSF of patients with viral meningitis (Lahrtz et al., 1997). RANTES, MIP-1, IL-15, and IL-16 were not or only occasionally detectable. Furthermore, Mig, a CXC chemokine which binds to the same receptor as IP-10 (Loetscher et al., 1996a), was not found in the CSF (Table 3). The
On the cellular source of chemokines in the central nervous system
The cellular sources of the chemokines detected in CSF of patients with meningitis are not known. Macrophages are the classical producers of MCP-1, IP-10 and IL-8 (Yoshimura et al., 1989; Luster et al., 1985). In analogy to experimental meningitis in mice (see above) it might be that both macrophages in the meninges and monocytes which are present in small numbers in normal CSF and in the choroid plexus become activated to produce IP-10, MCP-1 and IL-8 in the early course of infection. Besides
Final remarks
A much broader range of different chemokines is expressed in bacterial meningitis vs. viral meningitis. Furthermore, also quantitatively chemokines are present in the CSF in higher concentrations in bacterial than in viral meningitis. This goes in parallel with more pronounced chemotactic activity of bacterial meningitis CSF compared to viral meningitis CSF. Likewise, other cytokines including TNFα (Nadal et al., 1989), IL-1 (Lopez Cortes et al., 1993), IL-6 (Chavanet et al., 1992) or G-CSF (
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