Type I Interferon Signaling Exacerbates Chlamydia muridarum Genital Infection in a Murine Model

Epithelial cells lining the murine genital tract act as sentinels for microbial infection, play a major role in the initiation of the early inflammatory response, and can secrete factors that modulate the adaptive immune response when infected with Chlamydia. C. muridarum-infected murine oviduct epithelial cells secrete the inflammatory cytokines IL-6 and GM-CSF in a TLR2-dependent manner. Further, C. muridarum infection induces IFN-β synthesis in the oviduct epithelial cells in a TRIF-dependent manner. Because murine oviduct epithelial cells express TLR3 but not TLRs 4, 7, 8, or 9, we hypothesized that TLR3 or an unknown TRIF-dependent pattern recognition receptor was the critical receptor for IFN-β production. To investigate the role of TLR3 in the Chlamydia-induced IFN-β response in oviduct epithelial cells, we used small interfering RNA, dominant-negative TLR3 mutants, and TLR3-deficient oviduct epithelial cells to show that the IFN-β secreted during C. muridarum infection requires a functional TLR3. Interestingly, we demonstrate that the TLR3 signaling pathway is not required for IFN-β synthesis in C. muridarum-infected macrophages, suggesting that there are alternate and redundant pathways to Chlamydia-induced IFN-β synthesis that seem to be dependent upon the cell type infected. Finally, because there is no obvious dsRNA molecule associated with Chlamydia infection, the requirement for TLR3 in Chlamydia-induced IFN-β synthesis in infected oviduct epithelial cells implicates a novel ligand that binds to and signals through TLR3.

Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 69%

The Chlamydia muridarum-Induced IFN-β Response Is TLR3-Dependent in Murine Oviduct Epithelial Cells

Derbigny¹,

Johnson²,

Toomey³

et al. 2010

“…In viral or bacterial mouse infection models IFN-I promoted CD8 ϩ T cell expansion, but the magnitude of this effect varied strongly with the particular pathogen (25)(26)(27)(28). During Chlamydia infection production of IFN-I was negatively correlated with host immunity and suggested to cause suppression of T cell immunity (29).…”

mentioning

confidence: 99%

Dendritic Cells Require STAT-1 Phosphorylated at Its Transactivating Domain for the Induction of Peptide-Specific CTL

Pilz

Kratky

Stockinger

et al. 2009

Phosphorylation of transcription factor STAT-1 on Y701 regulates subcellular localization whereas phosphorylation of the transactivating domain at S727 enhances transcriptional activity. In this study, we investigate the impact of STAT-1 and the importance of transactivating domain phosphorylation on the induction of peptide-specific CTL in presence of the TLR9-dependent immune adjuvant IC31. STAT-1 deficiency completely abolished CTL induction upon immunization, which was strongly reduced in animals carrying the mutation of the S727 phospho-acceptor site. A comparable reduction of CTL was found in mice lacking the type I IFN (IFN-I) receptor, whereas IFN-γ-deficient mice behaved like wild-type controls. This finding suggests that S727-phosphorylated STAT-1 supports IFN-I-dependent induction of CTL. In adoptive transfer experiments, IFN-I- and S727-phosphorylated STAT-1 were critical for the activation and function of dendritic cells. Mice with a T cell-specific IFN-I receptor ablation did not show impaired CTL responses. Unlike the situation observed for CTL development S727-phosphorylated STAT-1 restrained proliferation of naive CD8+ T cells both in vitro and following transfer into Rag-deficient mice. In summary, our data reveal a dual role of S727-phosphorylated STAT-1 for dendritic cell maturation as a prerequisite for the induction of CTL activity and for T cell autonomous control of activation-induced or homeostatic proliferation.

“…C. trachomatis and the murine pathogen C. muridarum infect and replicate in epithelial cells and were found to induce IFN-b in a TLR3/TRIF-(117, 118) or cGAS/STING-dependent manner (119-121). Ifnar1-deficient mice exhibit reduced bacterial burden compared with WT mice following genital (122) and respiratory (123) infection with C. muridarum, revealing a detrimental role for type I IFNs in regulating mucosal immunity to this intracellular pathogen. However, type I IFNs do not appear to interfere with the development of a Th1 response to C. trachomatis because IL-12, TNF-a, and IFN-g expression were unaffected in both studies (122,123).…”

Section: Chlamydiamentioning

confidence: 99%

“…Ifnar1-deficient mice exhibit reduced bacterial burden compared with WT mice following genital (122) and respiratory (123) infection with C. muridarum, revealing a detrimental role for type I IFNs in regulating mucosal immunity to this intracellular pathogen. However, type I IFNs do not appear to interfere with the development of a Th1 response to C. trachomatis because IL-12, TNF-a, and IFN-g expression were unaffected in both studies (122,123). Instead, the increased resistance of Ifnar1 2/2 mice was found to be associated with reduced macrophage apoptosis, suggesting that type I IFNs impair host immunity by inducing the death of host-protective effector cells.…”

Section: Chlamydiamentioning

confidence: 99%

Interfering with Immunity: Detrimental Role of Type I IFNs during Infection

Stifter¹,

Feng²

2015

Type I IFNs are known to inhibit viral replication and mediate protection against viral infection. However, recent studies revealed that these cytokines play a broader and more fundamental role in host responses to infections beyond their well-established antiviral function. Type I IFN induction, often associated with microbial evasion mechanisms unique to virulent microorganisms, is now shown to increase host susceptibility to a diverse range of pathogens, including some viruses. This article presents an overview of the role of type I IFNs in infections with bacterial, fungal, parasitic, and viral pathogens and discusses the key mechanisms mediating the regulatory function of type I IFNs in pathogen clearance and tissue inflammation.