Interferon Regulatory Transcription Factor 3 Protects Mice from Uterine Horn Pathology during Chlamydia muridarum Genital Infection

Abstract

Mice with the type I interferon (IFN) receptor gene knocked out (IFNAR KO mice) or deficient for alpha/beta IFN (IFN-␣/␤) signaling clear chlamydial infection earlier than control mice and develop less oviduct pathology. Initiation of host IFN-␤ transcription during an in vitro chlamydial infection requires interferon regulatory transcription factor 3 (IRF3). The goal of the present study was to characterize the influence of IRF3 on chlamydial genital infection and its relationship to IFN-␤ expression in the mouse model. IRF3 KO mice were able to resolve infection as well as control mice, overcoming increased chlamydial colonization and tissue burden early during infection. As previously observed for IFNAR KO mice, IRF3 KO mice generated a potent antigen-specific T cell response. However, in contrast to IFNAR KO mice, IRF3 KO mice exhibited unusually severe dilatation and pathology in the uterine horns but normal oviduct pathology after infection. Although IFN-␤ expression in vivo was dependent on the presence of IRF3 early in infection (before day 4), the IFN-independent function of IRF3 was likely driving this phenotype. Specifically, early during infection, the number of apoptotic cells and the number of inflammatory cells were significantly less in uterine horns from IRF3 KO mice than in those from control mice, despite an increased chlamydial burden. To delineate the effects of IFN-␤ versus IRF3, neutralizing IFN-␤ antibody was administered to wild-type (WT) mice during chlamydial infection. IFN-␤ depletion in WT mice mimicked that in IFN〈R KO mice but not that in IRF3 KO mice with respect to both chlamydial clearance and reduced oviduct pathology. These data suggest that IRF3 has a role in protection from uterine horn pathology that is independent of its function in IFN-␤ expression.The obligate intracellular bacterium Chlamydia trachomatis is the most common cause of sexually transmitted bacterial infection in the world and can cause pelvic inflammatory disease and Fallopian tube pathology in women. The cellular paradigm for immune-mediated pathology posits that cytokines produced by persistently infected epithelial cells are necessary and sufficient for the development of pathology during chlamydial infection (49). This theory has generated interest in characterizing the types and classes of genes upregulated during infection (24,39,40,54). In addition to expressing proinflammatory genes, such as those for interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-␣), infected cells upregulate the type I IFNs (IFN-␣ and IFN-␤), which can signal via the common type I IFN receptor (IFN-␣/␤R) (29), leading to subsequent induction of a broad assortment of interferon-stimulatory genes (ISGs) (30). Using Chlamydia muridarum and the mouse female genital tract infection models, our laboratory demonstrated that signaling via IFN-␣/␤R was detrimental to the host during infection, as mice with the gene for IFN-␣/␤ signaling knocked out (IFNAR KO mice) cleared infection sooner than wild-type (WT) mice and developed l...

Absence of Specific Chlamydia trachomatis Inclusion Membrane Proteins Triggers Premature Inclusion Membrane Lysis and Host Cell Death

“…C. trachomatis encodes a diadylate cyclase which produces di-cyclic-AMP that is enriched in EBs and implicated in IFN responses in murine cells (Barker et al, 2013). Recent studies have demonstrated that both STING and cGAS are enriched in a punctate pattern in proximity to C. muridarum or C. trachomatis inclusions (Prantner et al, 2011; Barker et al, 2013; Zhang et al, 2014). We find that premature inclusion lysis results in a marked recruitment of STING and autophagosomal markers following inclusion lysis, which promotes activation of autophagy and host cell death.…”

The DNA Sensor, Cyclic GMP–AMP Synthase, Is Essential for Induction of IFN-β during Chlamydia trachomatis Infection

“…We and others have shown that type I IFN (IFNα and IFNβ) signaling exacerbates host pathology during the course of genital (4) or pulmonary (5) C. muridarum infection in the mouse model. Further, IFNβ depletion protects mice from oviduct pathology during genital chlamydial infection (6), demonstrating a significant contribution of IFNβ to host pathology. A similar detrimental effect of IFNβ signaling has been reported during other bacterial infections as well [reviewed in (7)].…”

Chlamydia muridarum Induction of Glandular Duct Dilation in Mice

“…Many previous mouse model-based studies grouped both hydrosalpinx and uterine horn dilation as upper genital tract pathology (19,20) and focused only on the fertility outcome (21)(22)(23) or patency of the upper genital tract (6) without differentiating uterine horn dilation from hydrosalpinx (8,(24)(25)(26)(27)(28). Although a previous study reported that interferon regulatory transcription factor 3 (IRF3) protected mice from uterine horn pathology during C. muridarum infection (13) and efforts have also been made to define host factors involved in C. muridarum induction of uterine horn dilation (29), the pathological basis of uterine horn dilation remains unclear. To understand whether and how C. muridarum infection induces uterine horn dilation and whether it can be used as a model for investigating C. trachomatis pathogenesis, we set out to define the pathological basis of uterine horn dilation in the current study.…”

“…Thus, the C. muridarum mouse genital tract infection model has been extensively used to investigate the mechanisms of C. trachomatis-induced hydrosalpinx in women. In addition to hydrosalpinx, dilation of the uterine horn has also been frequently detected in C. muridarum-infected mice (6,7,(10)(11)(12)(13)(14)(15). C. trachomatis genital tract infection in women is known to induce acute cervical and endometrial pathologies, including cervicitis and endometritis (16)(17)(18).…”