Abstract
IL-17 is believed to be important for protection against extracellular pathogens, where clearance is dependent on neutrophil recruitment and local activation of epithelial cell defences. However, the role of IL-17 in protection against intracellular pathogens such as Chlamydia is less clear. We have compared (i) the course of natural genital tract C. muridarum infection, (ii) the development of oviduct pathology and (iii) the development of vaccine-induced immunity against infection in wild type (WT) BALB/c and IL-17 knockout mice (IL-17-/-) to determine if IL-17-mediated immunity is implicated in the development of infection-induced pathology and/or protection. Both the magnitude and duration of genital infection was significantly reduced in IL-17-/- mice compared to BALB/c. Similarly, hydrosalpinx was also greatly reduced in IL-17-/- mice and this correlated with reduced neutrophil and macrophage infiltration of oviduct tissues. Matrix metalloproteinase (MMP) 9 and MMP2 were increased in WT oviducts compared to IL-17-/- animals at day 7 post-infection. In contrast, oviducts from IL-17-/- mice contained higher MMP9 and MMP2 at day 21. Infection also elicited higher levels of Chlamydia -neutralizing antibody in serum of IL-17-/- mice than WT mice. Following intranasal immunization with C. muridarum Major Outer Membrane Protein (MOMP) and cholera toxin plus CpG adjuvants, significantly higher levels of chlamydial MOMP-specific IgG and IgA were found in serum and vaginal washes of IL-17-/- mice. T cell proliferation and IFNγ production by splenocytes was greater in WT animals following in vitro re-stimulation, however vaccination was only effective at reducing infection in WT, not IL-17-/- mice. Intranasal or transcutaneous immunization protected WT but not IL-17-/- mice against hydrosalpinx development. Our data show that in the absence of IL-17, the severity of C. muridarum genital infection and associated oviduct pathology are significantly attenuated, however neither infection or pathology can be reduced further by vaccination protocols that effectively protect WT mice.
Highlights
The obligate, intracellular human pathogen Chlamydia trachomatis is the most common bacterial sexually transmitted disease worldwide and the cause of preventable blindness in developing countries (WHO 2007)
interleukin 17 (IL-17)-mediated activation of Matrix metalloproteinase (MMP) has been demonstrated to play a role in a number of inflammatory conditions including inflammation of mouse airways [25], cartilage destruction in mouse models of arthritis [26,27], hepatocellular carcinoma metastasis [28] and inflammation associated with human atherosclerosis [29], a condition that has been linked to C. pneumoniae infection [30]
Because IL-17 has been associated with the activation of MMPs in other inflammatory conditions, we investigated the expression of MMP2 and MMP9 in reproductive tract tissues of wild type (WT) and IL-17-/- mice following C. muridarum infection
Summary
The obligate, intracellular human pathogen Chlamydia trachomatis is the most common bacterial sexually transmitted disease worldwide and the cause of preventable blindness (trachoma) in developing countries (WHO 2007). More than 100 million new infections occur annually with untreated genital infection causing pelvic inflammatory disease (PID) in women and prostatitis in men, leading to infertility in both sexes. As Chlamydia has a bi-phasic developmental cycle, with both an extracellular and intracellular stage, and because the cytokine milieu necessary to activate Th17 cells in humans and mice is produced in response to a chlamydial genital infection [20], the role of Th17 cells during chlamydial infection is of interest. IL-17-mediated activation of MMPs has been demonstrated to play a role in a number of inflammatory conditions including inflammation of mouse airways [25], cartilage destruction in mouse models of arthritis [26,27], hepatocellular carcinoma metastasis [28] and inflammation associated with human atherosclerosis [29], a condition that has been linked to C. pneumoniae infection [30]
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