Abstract
BackgroundRegulation of immune responses is critical for controlling inflammation and disruption of this process can lead to tissue damage. We reported that CXCL13 was induced in fallopian tube tissue following C. trachomatis infection. Here, we examined the influence of the CXCL13-CXCR5 axis in chlamydial genital infection.Methodology and Principal FindingsDisruption of the CXCL13-CXCR5 axis by injecting anti-CXCL13 Ab to BALB/c mice or using Cxcr5−/− mice increased chronic inflammation in the upper genital tract (UGT; uterine horns and oviducts) after Chlamydia muridarum genital infection (GT). Further studies in Cxcr5−/− mice showed an elevation in bacterial burden in the GT and increased numbers of neutrophils, activated DCs and activated NKT cells early after infection. After resolution, we noted increased fibrosis and the accumulation of a variety of T cells subsets (CD4-IFNγ, CD4-IL-17, CD4-IL-10 & CD8-TNFα) in the oviducts. NKT cell depletion in vitro reduced IL-17α and various cytokines and chemokines, suggesting that activated NKT cells modulate neutrophils and DCs through cytokine/chemokine secretion. Further, chlamydial glycolipids directly activated two distinct types of NKT cell hybridomas in a cell-free CD1d presentation assay and genital infection of Cd1d−/− mice showed reduced oviduct inflammation compared to WT mice. CXCR5 involvement in pathology was also noted using single-nucleotide polymorphism analysis in C. trachomatis infected women attending a sub-fertility clinic. Women who developed tubal pathology after a C. trachomatis infection had a decrease in the frequency of CXCR5 SNP +10950 T>C (rs3922).Conclusions/SignificanceThese experiments indicate that disruption of the CXCL13-CXCR5 axis permits increased activation of NKT cells by type I and type II glycolipids of Chlamydia muridarum and results in UGT pathology potentially through increased numbers of neutrophils and T cell subsets associated with UGT pathology. In addition, CXCR5 appears to contribute to inter-individual differences in human tubal pathology following C. trachomatis infection.
Highlights
Chlamydia trachomatis, an obligate intracellular bacterium, causes the most cases of bacterial sexually transmitted infections (STIs) in the US resulting in about three million new cases annually [1,2,3]
We evaluated the chlamydial burden in the genital tract (GT) from vaginal swabs by using two models for disrupting the CXCL13-CXCR5 axis
Consistent with the increased bacterial burden we found increases in early immune responders such as neutrophils, activated CD40+ conventional dendritic cells (DC) and activated CD69+ NKT cells in the GT (Fig. 1C–E) but no difference was seen in the number of plasmacytoid DC cells which responds to C. muridarum genital infection [37]
Summary
An obligate intracellular bacterium, causes the most cases of bacterial sexually transmitted infections (STIs) in the US resulting in about three million new cases annually [1,2,3]. Genital infection can lead to immune-mediated damage of the female reproductive organs and serious reproductive disability, including pelvic inflammatory disease (PID) that can result in chronic pelvic pain, ectopic pregnancy and infertility. 8% of females annually develop PID and this risk increases by 40–70% following re-infection [3,4]. The mechanism(s) which causes PID and infertility following chlamydial genital infection is not known. The mouse model of C. trachomatis genital infection (C. muridarum) is used to reveal the underlying mechanism(s) for developing immune-mediated damage of the female reproductive organs following STIs. It is known that C. muridarum bacteria cause genital tract (GT) infections which trigger development of protective immune responses but infection results in GT inflammation and is associated with neutrophils and CD8 cells that produce TNFa [6,7,8]. We examined the influence of the CXCL13-CXCR5 axis in chlamydial genital infection
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