Borrelia gariniiInduces CXCL13 Production in Human Monocytes through Toll-Like Receptor 2

Abstract

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...

The proteoglycan biglycan regulates expression of the B cell chemoattractant CXCL13 and aggravates murine lupus nephritis

“…Cooperation of multiple signaling cascades with crucial roles of the canonical and the noncanonical NF-κB pathways has been postulated to be involved in the regulation of CXCL13 (48). Up to now, several inducers of CXCL13, including retinoic acid, IL-10, LPS, and Borrelia garinii, have been described (49)(50)(51). Among those, Borrelia garinii stimulates CXCL13 production via TLR2 (50).…”

“…Up to now, several inducers of CXCL13, including retinoic acid, IL-10, LPS, and Borrelia garinii, have been described (49)(50)(51). Among those, Borrelia garinii stimulates CXCL13 production via TLR2 (50). Involvement of LPS and TNFR-associated factor 6 (TRAF6) suggested a potential role of TLR4 in the induction of CXCL13 (49,52).…”

Has CXCL13 an Added Value in Diagnosis of Neurosyphilis?

“…CXCL13 has been demonstrated to be elevated in B lymphocyte-rich CSF (8,9). CSF CXCL13 has a higher sensitivity than the established diagnostic markers for neuroborreliosis, such as CSF pleocytosis and Borrelia-specific antibodies (10).…”

Neurosyphilis and Clinical Variants

“…However, the CSF examination is the only way to make the diagnosis of neurosyphilis, which may be a confounding factor when it is found normal cellularity or nonreactive VDRL. Studies searching for new diagnostic tools, such as the dosage in the CSF of B lymphocyte chemoattractant chemokine ligand 13 (CXCL13), but its applicability is not yet defined 6,23 , since this chemokine is also found in several other diseases 3 .…”