Biology subjects

Derbigny, W. A.

Publications and source records attributed to Derbigny, W. A..

4 recordsLinked to original sources

bioRxiv2026

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.

microbiology↗

bioRxiv2026

Interferon-β Coordinates Epithelial Immune Networks and Fibrotic Responses During Chlamydia muridarum Infection

Chlamydia trachomatis infection is the most common bacterial sexually transmitted infection worldwide and a leading cause of inflammatory reproductive tract disease and infertility in women. Much of the tissue damage associated with genital chlamydial infection arises from host inflammatory responses rather than direct bacterial cytotoxicity. Epithelial cells lining the female reproductive tract represent the primary host cells infected during chlamydial infection and play key roles in initiating innate immune responses. Among the cytokines produced by infected epithelial cells, type-I interferons have emerged as important regulators of host defense and inflammatory signaling; however, the specific contribution of interferon-{beta} (IFN-{beta}) to epithelial transcriptional responses during chlamydial infection remains incompletely defined. In the present study, we investigated the role of IFN-{beta} in coordinating epithelial immune signaling networks during infection with Chlamydia muridarum. Using wild-type murine oviduct epithelial cells (OE-WT) and IFN-{beta}-deficient epithelial cells (OE-IFN{beta}-KO), we performed pathway-focused RT{superscript 2} Profiler PCR array analyses examining transcriptional responses across four biological pathways: (1) innate and adaptive immune responses, (2) type-I interferon signaling, (3) inflammatory and autoimmune responses, and (4) fibrosis-associated pathways. Infection of OE-WT cells resulted in coordinated induction of cytokines, chemokines, and interferon-stimulated genes associated with antimicrobial defense and immune cell recruitment. In contrast, IFN-{beta} deficiency resulted in widespread dysregulation of these transcriptional programs, including reduced induction of interferon-responsive chemokines such as CCL5 and CXCL10, altered inflammatory cytokine expression, and transcriptional signatures consistent with enhanced tissue remodeling responses. Notably, IFN-{beta} deficiency resulted in increased TNF expression accompanied by reduced IL-6 induction, suggesting disruption of balanced inflammatory signaling networks. Pathway analyses further revealed dysregulated expression of fibrosis-associated genes including Serpine1, Ctgf, and Eng in IFN-{beta}-deficient epithelial cells, indicating potential mechanisms linking interferon signaling to tissue remodeling during infection. Collectively, these findings identify IFN-{beta} as a central regulator of epithelial immune networks during chlamydial infection and suggest that disruption of IFN-{beta} signaling may promote inflammatory and fibrotic pathology within the female reproductive tract. Author SummarySexually transmitted infections caused by Chlamydia trachomatis are a major cause of infertility worldwide. Although antibiotic treatment can eliminate the bacteria, damage to the reproductive tract often results from the bodys own immune response to infection. The epithelial cells lining the reproductive tract are the first cells infected and play an important role in initiating immune responses. In this study, we investigated how a specific immune signaling molecule, interferon-{beta} (IFN-{beta}), regulates the gene expression programs activated in epithelial cells during chlamydial infection. Using pathway-focused gene expression arrays, we found that IFN-{beta} coordinates multiple immune pathways, including interferon signaling, inflammatory cytokine networks, and genes associated with tissue remodeling. When IFN-{beta} was absent, many of these pathways became dysregulated, resulting in altered inflammatory signaling and gene expression patterns linked to fibrosis. These findings suggest that IFN-{beta} functions as a key regulator that helps balance protective immune responses with inflammatory processes that can damage reproductive tissues during infection.

microbiology↗

bioRxiv2019

TLR3 Deficiency Leads to Altered Immune Responses to Chlamydia trachomatis Infection in Human Oviduct Epithelial Cells

Reproductive tract pathology caused by Chlamydia trachomatis infection is an important global cause of human infertility. To better understand the mechanisms associated with Chlamydia-induced genital tract pathogenesis in humans, we used CRISPR genome editing to disrupt TLR3 function in the human oviduct epithelial (hOE) cell-line OE-E6/E7, in order to investigate the possible role(s) of TLR3 signaling in the immune response to Chlamydia. Disruption of TLR3 function in these cells significantly diminished the Chlamydia-induced synthesis of several inflammation biomarkers including IFN-{beta}, IL-6, IL-6Ra, sIL-6R{beta} (gp130), IL-8, IL-20, IL-26, IL-34, sTNF-R1, TNFSF13B, MMP-1, MMP-2, and MMP-3. In contrast, the Chlamydia-induced synthesis of CCL-5, IL-29 (IFN{lambda}1) and IL-28A (IFN{lambda}2) were significantly increased in the TLR3-deficient hOE cells when compared to their wild-type counterparts. Our results propose a role for TLR3 signaling in limiting the genital tract fibrosis, scarring, and chronic inflammation often associated with human chlamydial disease. Interestingly, we saw that Chlamydia infection induced the production of biomarkers associated with persistence, tumor metastasis, and autoimmunity such as soluble CD163 (sCD163), chitinase-3-like protein 1, osteopontin, and pentraxin-3 in the hOE cells; however, their expression levels were significantly dysregulated in the TLR3-deficient hOE cells. Finally, we demonstrate using the hOE cells that TLR3 deficiency resulted in an increased amount of chlamydial LPS within the Chlamydia inclusion, which is suggestive that TLR3 deficiency leads to enhanced chlamydial replication and possibly increased genital tract pathogenesis during human infection.\n\nAbbreviationshOE, human OE-E6/E7 cells; TLR3 KO, TLR3 knockout cell line; poly (I:C), Polyinosinic-polycytidylic acid sodium salt.

microbiology↗

bioRxiv2018

TLR3 deficiency exacerbates the loss of epithelial barrier function during genital tract Chlamydia muridarum infection

ProblemChlamydia trachomatis infections are often associated with acute syndromes including cervicitis, urethritis, and endometritis, which can lead to chronic sequalae such as pelvic inflammatory disease (PID), chronic pelvic pain, ectopic pregnancy, and tubal infertility. As epithelial cells are the major cell type productively infected during genital tract Chlamydia infections, we investigated whether Chlamydia has any impact on the integrity of the host epithelial barrier as a possible mechanism to facilitate the dissemination of infection, and examined whether TLR3 function modulates its impact.\n\nMethod of StudyWe used wild-type and TLR3-deficient murine oviduct epithelial (OE) cells to ascertain whether C. muridarum infection had any effect on the epithelial barrier integrity of these cells as measured by transepithelial resistance (TER) and cell permeability assays. We next assessed whether infection impacted the transcription and protein function of the cellular tight-junction (TJ) genes for claudins1-4, ZO-1, JAM1 and occludin via quantitative real-time PCR (qPCR) and western blot.\n\nResultsqPCR, immunoblotting, transwell permeability assays, and TER studies show that Chlamydia compromises cellular TJ function throughout the course of infection in murine OE cells, and that TLR3 deficiency significantly exacerbates this effect.\n\nConclusionOur data show that TLR3 plays a role in modulating epithelial barrier function during Chlamydia infection of epithelial cells lining the genital tract. This proposes a role for TLR3 signaling in maintaining the integrity of epithelial barrier function during genital tract Chlamydia infection, a function that we hypothesize is important in helping limit the chlamydial spread and subsequent genital tract pathology.

immunology↗