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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).

2019-01-31 | GSE108202 | GEO

Chlamydia trachomatis serogroup D disturbs epithelial tissue homeostasis in Fallopian tubes via paracrine Wnt signalling

Project description:Chlamydia trachomatis is the causative agent of sexually transmitted disease with the highest prevalence in the world today. Although, sensitive to antibiotic treatment, Ctr is also a major cause of infertility due to significant cell damage caused to the genital tract of affected women. Occlusion of Fallopian tubes is a frequent consequence of advanced ascending Ctr infection. So far the mechanisms of Ctr caused pathogensis are widely unclear. Here we show, by using an ex vivo infection model of human Fallopian tubes that Ctr causes changes in epithelial homeostasis within 2 days of inoculation, by disrupting cell adhesion and increasing cell proliferation. We demonstrate by imaging and expression analysis that tissue response to invading pathogen has also a paracrine component. We identify Wnt signalling activation as one of the hallmarks of Ctr infection which transmits effects of the infection beyond inclusion containing cells. Mechanisms of phenotypic changes involve up regulation of Epcam and Olfactomedin 4, biomarkers and regulators of cell adhesion and cell differentiation. Our findings bring focus to the pleiotropic effects of Ctr infection within epithelium and could be provide the basis for better understanding the pathological sequels in vivo.

2011-11-21 | GSE26692 | GEO

Chlamydia trachomatis serogroup D disturbs epithelial tissue homeostasis in Fallopian tubes via paracrine Wnt signalling

2011-11-21 | E-GEOD-26692 | biostudies-arrayexpress

MiRNA profiles of high grade serous papillary ovarian cancer tumors and normal fallopian tube epithelium

Project description:Fallopian tube epithelium is the tissue-of-origin of most high grade serous papillary ovarian carcinoma. This tumor has been exensively investigated and sequenced but expression profiling data of normal fallopian tube epithelial cells is still rare. This project compares the miRNA profiles of high grade serous papillary ovarian tumors (FFPE and fresh frozen) to that of normal unmatched epithelial cells from resected fallopian tubes.

2019-12-31 | GSE131790 | GEO

Comparison of gene expression profiling among high-grade ovarian epithelial cancer, ovarian epithelium and fallopian tube

Project description:Comparison of gene expression profiling among high-grade ovarian epithelial cancer, ovarian epithelium and fallopian tube which might indicate the origin and carcinogenesis of ovarian cancer

2017-08-01 | E-MTAB-3706 | biostudies-arrayexpress

Chronic Chlamydia trachomatis infection of fallopian tube organoids

Project description:Chronic Chlamydia trachomatis infection of fallopian tube organoids

| PRJNA422811 | ENA

Gene signatures of normal hTERT immortalized ovarian epithelium and fallopian tube epithelium (paired cultures from 2 donor patients)

Project description:Most epithelial ovarian cancers are thought to arise from different cells in the ovarian or fallopian tube epithelium. We hypothesized that these distinct cells-of-origin may play a role in determining ovarian tumor phenotype and also could inform the molecular classification of ovarian cancer. To test this hypothesis, we developed new methods to isolate and culture paired normal human ovarian (OV) and fallopian tube (FT) epithelial cells from multiple donors without cancer and identified a cell-of-origin gene expression signature that distinguished these cell types within the same patient. Application of the OV versus FT cell-of-origin gene signature to gene expression profiles of primary ovarian cancers permitted identification of distinct OV and FT-like subgroups among these cancers. Importantly, the normal FT-like tumor classification correlated with a significantly worse disease-free survival. This work describes a new experimental method for culture of normal human OV and FT epithelial cells from the same patient. These findings provide new evidence that cell-of-origin is an important source of ovarian tumor heterogeneity and the associated differences in tumor phenotype. We analyzed 12 samples from two donor patients and established cultures of both ovarian epithelium and fallopian tube epithelium (hTERT immortalized), each with 3 replicates (different culture passages).

2013-11-25 | E-GEOD-37648 | biostudies-arrayexpress

Integrative proteomic profiling of ovarian cancer cell lines reveals precursor-cell associated proteins and functional status

Project description:A cell line representative of human high-grade serous ovarian cancer (HGSOC) should not only resemble its tumor of origin at the molecular level, but also demonstrate functional utility in pre-clinical investigations. Here we report the integrated proteomic analysis of 26 ovarian cancer cell lines, HGSOC tumors, immortalized ovarian surface epithelial cells, and fallopian tube epithelial cells via a single-run mass spectrometric workflow. The in-depth quantitation of > 10,000 proteins results in three distinct cell line categories: epithelial (group I), clear cell (group II), and mesenchymal (group III). We identify a 67-protein cell line signature, which separates our entire proteomic dataset, as well as a confirmatory publicly available CPTAC/TCGA tumor proteome dataset, into a predominantly epithelial and mesenchymal HGSOC tumor cluster. This proteomics-based epithelial/mesenchymal stratification of cell lines and human tumors indicates a possible origin of HGSOC either from the fallopian tube or from the ovarian surface epithelium.

2016-08-24 | PXD003668 | Pride

RNAseq of small intestinal epithelium extracted from mice infected with Nippostrongylus brasiliensis

Project description:The intestinal epithelium is our first line of defense against infections of the gut and the plasticity in cellular differentiation of the intestinal epithelium is an important part of this response. Here we sequenced the small intestinal epithelium from mice infected with Nippostrongylus brasiliensis to determine how the intestinal epithelium adapts in the context of an infection. By comparing these data to small intestinal organoids treated with cytokines (see related accessions) we determine that the intestinal epithelial response to N. brasiliensis infection correspond to a type II infection driven by IL-13.

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RNAseq of colon intestinal epithelium extracted from mice infected with Citrobacter rodentium

Project description:The intestinal epithelium is our first line of defense against infections of the gut and the plasticity in cellular differentiation of the intestinal epithelium is an important part of this response. Here we sequenced the colon intestinal epithelium from mice infected with Citrobacter rodentium to determine how the intestinal epithelium adapts in the context of an infection. By comparing these data to small intestinal organoids treated with cytokines (see related accessions) we determine that the intestinal epithelial response to C. rodentium infection correspond to a type III infection driven by IL22.

2022-05-08 | E-MTAB-9184 | biostudies-arrayexpress

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