Recent studies have suggested an important role for the B-cell-attracting chemokine CXCL13 in the B-cell-dominated cerebrospinal fluid (CSF) infiltrate in patients with neuroborreliosis (NB). High levels of CXCL13 were present in the CSF of NB patients. It has not been clear, however, whether high CSF CXCL13 titers are specific for NB or are a characteristic of other spirochetal diseases as well. Furthermore, the mechanisms leading to the observed CXCL13 expression have not been identified yet. Here we describe similarly elevated CSF CXCL13 levels in patients with neurosyphilis, while pneumococcal meningitis patient CSF do not have high CXCL13 levels. In parallel, challenge of human monocytes in vitro with two of the spirochetal causative organisms, Borrelia garinii (the Borrelia species most frequently found in NB patients) and Treponema pallidum, but not challenge with pneumococci, induced CXCL13 release. This finding implies that a common spirochetal motif is a CXCL13 inducer. Accordingly, we found that the lipid moiety N-palmitoyl-S-(bis[palmitoyloxy]propyl)cystein (Pam 3 C) (three palmitoyl residues bound to N-terminal cysteine) of the spirochetal lipoproteins is critical for the CXCL13 induction in monocytes. As the Pam 3 C motif is known to signal via Toll-like receptor 2 (TLR2) and an anti-TLR2 monoclonal antibody blocked CXCL13 production of human monocytes incubated with B. garinii, this suggests that TLR2 is a major mediator of Borrelia-induced secretion of CXCL13 from human monocytes.Spirochetes are a group of bacteria that can be distinguished morphologically from other bacteria based on the fact that they are thin, long, and helical or corkscrew shaped. While in the northern hemisphere Borrelia burgdorferi is the predominant spirochete responsible for neuroinfectious diseases, infections of the central nervous system (CNS) with Treponema pallidum are endemic in regions all over the world. Moreover, a dramatic increase in the incidence of syphilis has been noted in several countries (9). In contrast to their high prevalence, the pathogenesis of neuroborreliosis (NB) and neurosyphilis (NS) is not yet well understood. After crossing the blood-brain barrier, both spirochetes elicit an inflammatory response in the cerebrospinal fluid (CSF), predominantly mediated by mononuclear cells. This contrasts with the massive invasion of polymorphonuclear cells into the CSF of patients with pneumococcal meningitis (PM), the most frequent bacterial infection of the adult CNS.It is assumed that the infiltration and the composition of the immunocompetent cells in the CSF are mainly the result of the intrathecal production of chemokines. Besides being grouped according to common motifs in their amino acid sequences, chemokines can be subdivided according to the cell populations that they predominantly attract. B lymphocytes, in contrast to other leukocytes, show substantial migration in response to only a very few chemokines, namely, CCL19, CCL21, CXCL12, and CXCL13 (3). Since the proportion of B lymphocytes in the C...

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Endogenous molecules released from disrupted cells and extracellular matrix degradation products activate Toll-like receptors (TLRs) and, thus, might contribute to immune activation after tissue injury. Here, we show that aseptic, cold-induced cortical injury triggered an acute immune response that involves increased production of multiple cytokines/chemokines accompanied by neutrophil recruitment to the lesion site. We observed selective reductions in injury-induced cytokine/chemokine expression as well as in neutrophil accumulation in mice lacking the common TLR signaling adaptor MyD88 compared with wild-type mice. Notably , attenuation of the immune response was paralleled by a reduction in lesion size. Neutrophil depletion of wild-type mice and transplantation of MyD88-deficient bone marrow into lethally irradiated wild-type recipients had no substantial impact on injury-induced expression of cytokines/chemokines and on lesion development. In contrast to MyD88 deficiency , double deficiency of TLR2 and TLR4 -despite the two receptors being activated by specific endogenous molecules associated to danger and signal through MyD88 -altered neither immune response nor extent of tissue lesion size on injury. Our data indicate modulation of the neuroinflammatory response and lesion development after aseptic cortical injury through MyD88-dependent but TLR2/4-independent signaling by central nervous system resident nonmyeloid cells.

Tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) have been suggested to play an important role in inflammatory diseases. Increased levels of tPA, uPA, uPA receptor (uPAR), and their inhibitor, plasminogen activator inhibitor (PAI)-1, have been found in the cerebrospinal fluid (CSF) of patients with bacterial meningitis. Here, we show that expression of tPA, uPA, uPAR, PAI-1, and PAI-2 is up-regulated during experimental pneumococcal meningitis. In uPAR-deficient mice, CSF pleocytosis was significantly attenuated 24 h after infection, compared with that in infected wild-type (wt) mice. Lack of uPAR did not influence blood-brain barrier permeability, intracranial pressure, expression of chemokines (keratinocyte-derived cytokine and macrophage inflammatory protein-2), bacterial killing, or clinical outcome. No differences in pathophysiological alterations were observed in tPA-deficient mice, compared with those in infected wt mice. These results indicate that uPAR participates in the recruitment of leukocytes to the CSF space during pneumoccal meningitis.

Hearing loss is one of the most common sequelae in survivors of pneumococcal meningitis, affecting up to 26% of them. Here, we established the first mouse model of meningitis-associated hearing loss and investigated the role played by the Toll-like receptor-associated adapter molecule MyD88. C57BL/6 mice were infected intracisternally by Streptococcus pneumoniae. By use of audiometry and histological analysis, cochleae were assessed in uninfected control mice during the acute stage and after recovery. MyD88-deficient mice were analyzed 24 h after infection. Wild-type mice lost hearing capacity to a significant degree, which was accompanied by a granulocytic cochlear inflammation. After recovery, hearing loss was still evident, and spiral ganglion neuronal loss, hair cell damage, and fibrocytic occlusion of the cochlea were observed. In contrast, mice lacking MyD88 developed significantly less hearing loss and had diminished cochlear inflammation. Our results strongly suggest a proinflammatory role for MyD88 in the initiation of the inflammatory response during pneumococcal meningitis-associated labyrinthitis.