Abstract
Chronic infections of the fallopian tubes with Chlamydia trachomatis (Ctr) cause scarring and can lead to infertility. Here we use human fallopian tube organoids and genital Ctr serovars D, K and E for long-term in vitro analysis. The epithelial monolayer responds with active expulsion of the bacteria into the lumen and with compensatory cellular proliferation—demonstrating a role of epithelial homeostasis in the defense against this pathogen. In addition, Ctr infection activates LIF signaling, which we find to be an essential regulator of stemness in the organoids. Infected organoids exhibit a less differentiated phenotype with higher stemness potential, as confirmed by increased organoid forming efficiency. Moreover, Ctr increases hypermethylation of DNA, which is an indicator of accelerated molecular aging. Thus, the chronic organoid infection model suggests that Ctr has a long-term impact on the epithelium. These heritable changes might be a contributing factor in the development of tubal pathologies, including the initiation of high grade serous ovarian cancer.
Highlights
Chronic infections of the fallopian tubes with Chlamydia trachomatis (Ctr) cause scarring and can lead to infertility
We report the establishment of a chronic Ctr infection model of fallopian tube (FT) organoids with genital serovars D, K, and E, which are the major drivers of tubal pathology in vivo
In stark contrast to conventional infection models based on transformed cell lines, which allow Ctr propagation for only a single life cycle due to lysis of infected cells, the organoids accommodated the bacteria for extended periods of time and continued to expand at a normal rate, despite an ongoing productive infection
Summary
Chronic infections of the fallopian tubes with Chlamydia trachomatis (Ctr) cause scarring and can lead to infertility. The chronic organoid infection model suggests that Ctr has a long-term impact on the epithelium. These heritable changes might be a contributing factor in the development of tubal pathologies, including the initiation of high grade serous ovarian cancer. It has so far been impossible to analyze the molecular sequels of these initial events during the establishment of chronic Ctr infections in the human model It is unclear if protracted microbial colonization of the tube adds to the risk of cellular transformation and ovarian cancer development, since the epidemiological data remain inconsistent[11,12]. We identify sustained pathogen-driven changes in cellular differentiation of the epithelium that occur over the course of 9 months of infection, showing that Ctr alters the phenotype of host cells and leaves a lasting mark in the epigenome
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
