Examining the impact of the Chlamydia muridarum-induced synthesis of IFN-β during genital tract infection

Chlamydia trachomatis infection of the female genital tract can result in severe reproductive sequelae, including pelvic inflammatory disease, tubal scarring, and infertility. Type I interferons have been implicated in both host defense and immunopathogenesis during chlamydial infection, with conflicting conclusions across experimental systems. However, the specific contributions of individual interferon subtypes remain poorly defined. Here, we examined the role of interferon beta (IFN-{beta}) in regulating epithelial immune responses and intracellular bacterial development during Chlamydia muridarum infection. Using murine oviduct epithelial (OE) cell lines derived from wild-type, IFN{beta}-deficient, and Toll-like receptor 3 (TLR3)-deficient mice, we demonstrate that IFN-{beta} is a critical epithelial-intrinsic mediator of host defense. Loss of IFN-{beta} led to dysregulation of genes associated with inflammation, immune regulation, and fibrosis, altered chlamydial inclusion morphology, enhanced expression of bacterial genes throughout the chlamydial developmental cycle, and increased chlamydial replication. Importantly, exogenous IFN-{beta} restored both immune mediator production and bacterial control during IFN{beta}-deficiency. Parallel analyses revealed that TLR3 deficiency phenocopied IFN-{beta} loss, supporting a TLR3-IFN-{beta} signaling axis that restricts chlamydial growth. Consistent with these in vitro findings, IFN{beta}-deficient mice exhibited enhanced bacterial burden during genital tract infection. Together, these data establish IFN-{beta} as a protective epithelial mediator during chlamydial infection and demonstrate that type I interferon responses are not functionally uniform. Our findings provide a mechanistic framework to reconcile the protective role of IFN-{beta} with reports of reduced pathology in interferon-/{beta} receptor-deficient models and highlight the importance of dissecting individual interferon pathways in chlamydial immunopathogenesis. ImportanceGenital tract infection with Chlamydia trachomatis remains a leading cause of preventable infertility worldwide. Although type I interferons are widely viewed as contributors to chlamydial pathology, most studies have examined global interferon signaling rather than the roles of individual interferon subtypes. In this study, we demonstrate that interferon beta (IFN-{beta}) plays a protective, epithelial-intrinsic role during chlamydial infection by restricting bacterial development and shaping local immune responses. These findings challenge the prevailing view that type I interferons are uniformly detrimental in this setting and reveal that distinct interferon subtypes can exert opposing effects on host defense and disease outcome. By defining a TLR3-IFN-{beta} signaling axis that limits chlamydial replication, this work advances our understanding of epithelial immunity in the female genital tract and has important implications for the design of targeted immunomodulatory strategies to prevent chlamydia-induced reproductive pathology.