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Chronic Chlamydia infection in fallopian tube organoids alters epithelial differentiation and accelerate methylation changes

ABSTRACT: Chlamydia trachomatis (Ctr) is able to colonize the human fallopian tube, causing scarring and inflammation, which can lead to infertility. Here we describe a chronic Ctr infection model using human fallopian tube organoids. The defense response of the organoids to infection includes active expulsion of the bacteria from the apical side of the epithelium and compensatory cellular proliferation, clearly demonstrating a role for core mechanisms of epithelial homeostasis in defense against this invading pathogen. During progression in culture for over 9 months, the population of epithelial cells underwent a permanent shift towards a more dedifferentiated state. We identify LIF signaling an essential for regulation of the stemness in the tube and formation of organoids, and report its activation triggered by Ctr . In the long term, chronic Ctr infection leads to changes in the composition of the epithelium, marked by an increase in the proportion of secretory cells, expansion of the CD24+ positive population, upregulation of SPP1 factor, as well as downregulation of inflammatory mediators CD90, CD83, and CCR7. Ctr increases hypermethylation of DNA in polycomb repressed genomic regions - indicator of accelerated molecular aging. This infection model reveals an important link between Ctr and regulation of the host epigenome and suggests that Ctr has a long-term impact on the epithelial interaction with the immune system. These permanent changes in the epithelium may be a contributing factor in the development of tubal pathologies, particularly development of high grade serous ovarian cancer (HGSOC).

ORGANISM(S): Homo sapiens

PROVIDER: GSE107712 | GEO | 2019/01/31

REPOSITORIES: GEO

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Chronic Chlamydia trachomatis infection of fallopian tube organoids

Project description:Chronic infections of the Fallopian tubes with Chlamydia trachomatis (Ctr) can cause scarring and inflammation and can lead to infertility. Here we describe a model of human fallopian tube organoids for chronic Ctr infection. Interestingly, the normal human cells respond to infection with an active expulsion of the bacteria from the apical side of the epithelium and compensatory cellular proliferation clearly demonstrating a role of epithelial homeostasis in the defense against this infectious agent. Upon progression of the infected culture for over 9 months, the population of epithelial cells underwent a permanent shift towards a less differentiated state. LIF signaling is an essential feature, regulating stemness in the tube and organoid formation, and is activated in response to Ctr. Hallmarks of an organoid infection include a relative increase of secretory cells, expansion of the CD24+ positive population, upregulation of SPP1 factor, as well as downregulation of HOXA4 and HOXA5 homeobox genes. Moreover, Ctr increases hypermethylation of DNA in polycomb repressed genomic regions, an indicator of accelerated molecular aging. This infection model reveals an intriguing link between Ctr and regulation of the host epigenome and suggests that this pathogen has a long-term impact on the interaction of the epithelium with the microenviroment. These permanent changes in the epithelium may be a contributing factor in the development of tubal pathologies, including the development of high grade serous ovarian cancer (HGSOC).

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