The Duration of Chlamydia muridarum Genital Tract Infection and Associated Chronic Pathological Changes Are Reduced in IL-17 Knockout Mice but Protection Is Not Increased Further by Immunization

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.

Signaling via Tumor Necrosis Factor Receptor 1 but Not Toll-Like Receptor 2 Contributes Significantly to Hydrosalpinx Development following Chlamydia muridarum Infection

“…The reduced hydrosalpinx was further correlated with a significant reduction in IL-17 production by splenocytes from TNFR1 Ϫ/Ϫ mice. This finding is supported by a recent observation that mice deficient in IL-17 developed significantly reduced chronic pathology (45) and also is consistent with our previous study showing that although the IL-23/TH17 axis was not required for host resistance to C. muridarum infection, it contributed significantly to Chlamydia-induced pathology (20). These observations together have suggested that IL-17-mediated responses are critical for hydrosalpinx development during C. muridarum infection.…”

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“…[8] However,Lu et al have shown that defense from genital infection by means of live Chlamydia immunization correlates with Т-cell response and is characterized by IFNγ high level and IL-17 low level. [9] Andrew et al in their investigation have illustrated that, in IL-17 absence, clinical gravity in chlamydial genital lesions is considerably lessened; [10] like this, in our study, IL-17 level in the chlamydial infection group was not different from the control values.…”

Complement Factor C5 but Not C3 Contributes Significantly to Hydrosalpinx Development in Mice Infected with Chlamydia muridarum

“…The same study also revealed that tumor necrosis factor receptor 1 (TNFR1) was critical for hydrosalpinx development following C. muridarum infection, which is consistent with an earlier observation showing an important role of tumor necrosis factor alpha (TNF-␣) in chlamydial induction of hydrosalpinx (14). Many other host molecules have also been shown to contribute to chlamydial pathogenicity in the upper genital tract, including matrix metalloproteinases (15), inducible nitric oxide synthase (16), interleukin 1 (IL-1) receptor (17), caspase 1 (18,19), IL-17 (20), CD28 (21), and CXCR2 (22). However, none of these previous studies have sufficiently addressed whether the reduced pathology was due to reduced oviduct infection, reduced inflammatory responses in the oviduct, or both.…”