Mechanisms of pro-fibrotic gene expression of endocervical epithelial cells during infection by Chlamydia trachomatis

Liam Thomas Caven

doi:10.7273/000005143

Chlamydia trachomatis is the most common source of bacterial sexually transmitted disease worldwide. An obligate intracellular pathogen, C. trachomatis invades epithelial cells of the upper female genital tract. Repeated acute or chronic C. trachomatis infections can lead to fibrotic sequelae, such as tubal factor infertility and ectopic pregnancy. Fibrosis is understood as an outcome of dysregulated wound healing. Aberrant activation of myofibroblasts promotes deposition of fibrillar collagens in the extracellular matrix, producing a stiffened basement membrane that further drives myofibroblast differentiation. C. trachomatis infection is shown to stimulate host cell production of pro-fibrotic signal factors and induce myofibroblast differentiation via an epithelial-to-mesenchymal transition (EMT). However, it remains unclear how C. trachomatis drives the host pro-fibrotic gene expression associated with these phenotypes.C. trachomatis productively infects transitional and undifferentiated epithelial cells of the ectocervix, yet scarring of the lower female genital tract has not been reported. In contrast, infection of the simple columnar epithelium of the upper genital tract can promote fibrosis, with a local pro-inflammatory response acting as a predisposing cofactor. One plausible explanation for this discrepancy is that endocervical epithelial cells are intrinsically predisposed towards pro-fibrotic gene expression. To investigate this possibility, I compared transcriptomes of primary human endocervical and vaginal epithelial cells. The former exhibited induction of pro-EMT transcription factors and repression of cytokeratins regardless of infection state, suggesting predisposition towards chlamydial induction of EMT. Further study of the host transcriptome determined that C. trachomatis activates the transcriptional cofactor YAP, inducing expression of pro-fibrotic signal factors. Chlamydial YAP induction seemingly bypasses YAP inhibition by the Hippo kinase cascade, acting instead via enhancement of YAP phosphoactivation dependent upon host Src-family kinases and the chlamydial effector CTL0480. To determine if infection-associated signaling promotes myofibroblast activation, I developed an in vitro model for study of communication between C. trachomatis-infected endocervical epithelial cells and neighboring fibroblasts. Cocultured fibroblasts exhibited induction of fibrillar type I collagen – a phenotype attenuated by YAP knockdown in epithelial cells. Collectively, these results introduce a means by which C. trachomatis induces pro-fibrotic gene expression and identify YAP as a potential therapeutic target for infection-associated fibrosis.

Mechanisms of pro-fibrotic gene expression of endocervical epithelial cells during infection by Chlamydia trachomatis

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