{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:57:34Z","timestamp":1768507054545,"version":"3.49.0"},"posted":{"date-parts":[[2023,5,31]]},"group-title":"Cell Biology","reference-count":95,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,5,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Infection of the female genital tract by\n                  <jats:italic>Chlamydia trachomatis<\/jats:italic>\n                  can produce severe fibrotic sequelae, including tubal factor infertility and ectopic pregnancy. While infection demonstrably mediates a pro-fibrotic response in host cells, it remains unclear if intrinsic properties of the upper genital tract exacerbate chlamydial fibrosis. The relatively sterile environment of the upper genital tract is primed for a pro-inflammatory response to infection, potentially enhancing fibrosis - however, subclinical\n                  <jats:italic>C. trachomatis<\/jats:italic>\n                  infections still develop fibrosis-related sequelae. Here, we compare infection-associated and steady-state gene expression of primary human cervical and vaginal epithelial cells. In the former, we observe enhanced baseline expression and infection-mediated induction of fibrosis-associated signal factors (e.g.\n                  <jats:italic>TGFA<\/jats:italic>\n                  ,\n                  <jats:italic>IL6<\/jats:italic>\n                  ,\n                  <jats:italic>IL8<\/jats:italic>\n                  ,\n                  <jats:italic>IL20<\/jats:italic>\n                  ), implying predisposition to\n                  <jats:italic>Chlamydia<\/jats:italic>\n                  -associated pro-fibrotic signaling. Transcription factor enrichment analysis identified regulatory targets of YAP, a transcriptional cofactor induced by infection of cervical epithelial cells, but not vaginal epithelial cells. YAP target genes induced by infection include secreted fibroblast-activating signal factors; therefore, we developed an\n                  <jats:italic>in vitro<\/jats:italic>\n                  model involving coculture of infected endocervical epithelial cells with uninfected fibroblasts. Coculture enhanced fibroblast expression of type I collagen, as well as prompting reproducible (albeit statistically insignificant) induction of \u03b1-smooth muscle actin. Fibroblast collagen induction was sensitive to siRNA-mediated YAP knockdown in infected epithelial cells, implicating chlamydial YAP activation in this effect. Collectively, our results present a novel mechanism of fibrosis initiated by\n                  <jats:italic>Chlamydia,<\/jats:italic>\n                  wherein infection-mediated induction of host YAP facilitates pro-fibrotic intercellular communication. Chlamydial YAP activation in cervical epithelial cells is thus a determinant of this tissue\u2019s susceptibility to fibrosis.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Importance<\/jats:title>\n                  <jats:p>\n                    Chronic or repeated infection of the female upper genital tract by\n                    <jats:italic>C. trachomatis<\/jats:italic>\n                    can lead to severe fibrotic sequelae, including tubal factor infertility and ectopic pregnancy. However, the molecular mechanisms underlying this effect are unclear. In this report, we define a transcriptional program specific to\n                    <jats:italic>C. trachomatis<\/jats:italic>\n                    infection of the upper genital tract, identifying tissue-specific induction of host YAP \u2013 a pro-fibrotic transcriptional cofactor \u2013 as a potential driver of infection-mediated fibrotic gene expression. Further, we show that infected endocervical epithelial cells stimulate collagen production by fibroblasts, and implicate chlamydial induction of YAP in this effect. Our results define a mechanism by which infection mediates tissue-level fibrotic pathology via paracrine signaling, and identify YAP as a potential therapeutic target for prevention of\n                    <jats:italic>Chlamydia<\/jats:italic>\n                    -associated scarring of the female genital tract.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2023.05.30.542940","type":"posted-content","created":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T19:05:12Z","timestamp":1685559912000},"source":"Crossref","is-referenced-by-count":1,"title":["Chlamydial YAP activation in host endocervical epithelial cells mediates pro-fibrotic paracrine stimulation of fibroblasts"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8321-4770","authenticated-orcid":false,"given":"Liam","family":"Caven","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5708-5493","authenticated-orcid":false,"given":"Rey","family":"Carabeo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023060212401425000_2023.05.30.542940v1.1","doi-asserted-by":"crossref","first-page":"e72","DOI":"10.1097\/OLQ.0000000000000858","article-title":"The Proportion of Young Women Tested for Chlamydia Who Had Urogenital Symptoms in Physician Offices","volume":"45","year":"2018","journal-title":"Sex Transm Dis"},{"key":"2023060212401425000_2023.05.30.542940v1.2","doi-asserted-by":"publisher","DOI":"10.1086\/652395"},{"key":"2023060212401425000_2023.05.30.542940v1.3","doi-asserted-by":"publisher","DOI":"10.1097\/OLQ.0b013e3181557c25"},{"key":"2023060212401425000_2023.05.30.542940v1.4","first-page":"3164","article-title":"The association between Chlamydia trachomatis and ectopic pregnancy","volume":"263","year":"1990","journal-title":"A matched-pair, case-control study.JAMA"},{"key":"2023060212401425000_2023.05.30.542940v1.5","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1055\/s-0042-1748023","article-title":"The Correlation between Chlamydia trachomatis and Female Infertility: A Systematic Review","volume":"44","year":"2022","journal-title":"Rev Bras Ginecol Obstet"},{"key":"2023060212401425000_2023.05.30.542940v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(16)30092-5"},{"key":"2023060212401425000_2023.05.30.542940v1.7","doi-asserted-by":"publisher","DOI":"10.3310\/hta20220"},{"key":"2023060212401425000_2023.05.30.542940v1.8","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119136"},{"key":"2023060212401425000_2023.05.30.542940v1.9","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.70.6.3234-3248.2002"},{"key":"2023060212401425000_2023.05.30.542940v1.10","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.69.3.1420-1427.2001"},{"key":"2023060212401425000_2023.05.30.542940v1.11","doi-asserted-by":"publisher","DOI":"10.1186\/s12866-014-0277-4"},{"key":"2023060212401425000_2023.05.30.542940v1.12","doi-asserted-by":"crossref","unstructured":"Caven, L. 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