The role of infected epithelial cells in Chlamydia-associated fibrosis

Abstract

Ocular, genital, and anogenital infection by the obligate intracellular pathogen Chlamydia trachomatis have been consistently associated with scar-forming sequelae. In cases of chronic or repeated infection of the female genital tract, infection-associated fibrosis of the fallopian tubes can result in ectopic pregnancy or infertility. In light of this urgent concern to public health, the underlying mechanism of C. trachomatis-associated scarring is a topic of ongoing study. Fibrosis is understood to be an outcome of persistent injury and/or dysregulated wound healing, in which an aberrantly activated myofibroblast population mediates hypertrophic remodeling of the basement membrane via deposition of collagens and other components of the extracellular matrix, as well as induction of epithelial cell proliferation via growth factor signaling. Initial study of infection-associated immune cell recruitment and pro-inflammatory signaling have suggested the cellular paradigm of chlamydial pathogenesis, wherein inflammation-associated tissue damage and fibrosis are the indirect result of an immune response to the pathogen initiated by host epithelial cells. However, recent work has revealed more direct routes by which C. trachomatis may induce scarring, such as infection-associated induction of growth factor signaling and pro-fibrotic remodeling of the extracellular matrix. Additionally, C. trachomatis infection has been shown to induce an epithelial-to-mesenchymal transition in host epithelial cells, prompting transdifferentiation into a myofibroblast-like phenotype. In this review, we summarize the field's current understanding of Chlamydia-associated fibrosis, reviewing key new findings and identifying opportunities for further research.

Keywords: Chlamydia trachomatis; ECM; EMT; fibrosis; host-pathogen interaction; pathogenesis.

Figure 1

Schematic representation of fibrosis. Injury stimulates the recruitment of immune cells and differentiation of myofibroblasts at the wound side, facilitating the deposition of a provisional extracellular matrix (ECM) acting as a scaffold for epithelial cell migration and proliferation in closing the wound. Wound healing terminates with the cessation of inflammation and growth factor signaling, prompting reversion or apoptosis of myofibroblasts. Chronic inflammation or repeated injury leads to persistent myofibroblast activation. This in turn promotes excessive deposition of ECM components, epithelial cell proliferation, and ultimately fibrosis.

Figure 2

Diagram of pro-fibrotic intercellular communication. Tissue injury prompts secretion of signal factors at the wound site, including pro-inflammatory cytokines (e.g. IL-1β, IL-6/8) and growth factors (e.g. TGFβ, EGF, CTGF), driving the proliferation of activated myofibroblasts via induction of fibroblast differentiation or epithelial-to-mesenchymal transition (EMT). Cytokine-mediated recruitment of immune cells (e.g. M.2 macrophages, neutrophils, dendritic cells) and their subsequent expression of myofibroblast-activating signal factors contributes to this effect. Deposition of collagens and other extracellular matrix (ECM) components by myofibroblasts and ECM-restructuring enzymes by both epithelial cells and myofibroblasts produces basement membrane stiffening and pro-fibrotic cytokines, further driving myofibroblast activation in a positive feedback loop via the action of ECM-derived matrikines and mechanotransduction. Importantly, multiple inhibitors of fibrosis-associated signaling have been identified (Li et al., 2017; Zhao et al., 2022), including the TGFβ antagonist pirfenidone (Antoniu, 2006), the EGFR inhibitor erlotinib (Fuchs et al., 2014), the anti-CTGF recombinant antibody pamrevlumab (Richeldi et al., 2020), the PGDF receptor kinase inhibitor BIBF-1000 (Chaudhary et al., 2007), the myofibroblast-inhibitory hormone relaxin (Samuel et al., 2014; Huuskes et al., 2015), the Wnt/β-catenin antagonist PRI-724 (Akcora et al., 2018), the MMP inhibitor batimastat (Corbel et al., 2001), the IL-1βR antagonist rilonacept (Li et al., 2017), and the soluble IL-6 receptor sIL-6Rα (Le et al., 2014).