Chronic Chlamydia infection in human organoids increases stemness and promotes age-dependent CpG methylation

Nat Commun. 2019 Mar 18;10(1):1194. doi: 10.1038/s41467-019-09144-7.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Age Factors
  • Chlamydia Infections / genetics*
  • Chlamydia Infections / immunology
  • Chlamydia Infections / microbiology
  • Chlamydia trachomatis / genetics
  • Chlamydia trachomatis / immunology*
  • Chronic Disease
  • CpG Islands / genetics*
  • CpG Islands / immunology
  • Cystadenocarcinoma, Serous / genetics
  • Cystadenocarcinoma, Serous / immunology
  • Cystadenocarcinoma, Serous / microbiology
  • DNA Methylation / immunology*
  • Epigenesis, Genetic / genetics
  • Epigenesis, Genetic / immunology
  • Epithelium / immunology
  • Epithelium / metabolism
  • Epithelium / microbiology
  • Fallopian Tubes / immunology
  • Fallopian Tubes / metabolism
  • Fallopian Tubes / microbiology
  • Female
  • Host Microbial Interactions / genetics*
  • Host Microbial Interactions / immunology
  • Humans
  • Intravital Microscopy
  • Microscopy, Confocal
  • Organoids / immunology
  • Organoids / metabolism
  • Organoids / microbiology
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / immunology
  • Ovarian Neoplasms / microbiology
  • Serogroup
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Single-Cell Analysis
  • Stem Cells / immunology
  • Stem Cells / metabolism*
  • Stem Cells / microbiology
  • Tissue Culture Techniques