Molecular Pathogenesis of Chlamydia Disease Complications: Epithelial-Mesenchymal Transition and Fibrosis.
The reproductive system complications of genital chlamydial infection include fallopian tube fibrosis and tubal factor infertility. However, the molecular pathogenesis of these complications remains poorly understood. The induction of pathogenic epithelial-mesenchymal transition (EMT) through microRNA (miRNA) dysregulation was recently proposed as the pathogenic basis of chlamydial complications. Focusing on fibrogenesis, we investigated the hypothesis that chlamydia-induced fibrosis is caused by EMT-driven generation of myofibroblasts, the effector cells of fibrosis that produce excessive extracellular matrix (ECM) proteins. The results revealed that the targets of a major category of altered miRNAs during chlamydial infection are key components of the pathophysiological process of fibrogenesis; these target molecules include collagen types I, III, and IV, transforming growth factor β (TGF-β), TGF-β receptor 1 (TGF-βR1), connective tissue growth factor (CTGF), E-cadherin, SRY-box 7 (SOX7), and NFAT (nuclear factor of activated T cells) kinase dual-specificity tyrosine (Y) phosphorylation-regulated kinase 1a (Dyrk1a). Chlamydial induction of EMT resulted in the generation of α-smooth muscle actin (α-SMA)-positive myofibroblasts that produced ECM proteins, including collagen types I and III and fibronectin. Furthermore, the inhibition of EMT prevented the generation of myofibroblasts and production of ECM proteins during chlamydial infection. These findings may provide useful avenues for targeting EMT or specific components of the EMT pathways as a therapeutic intervention strategy to prevent chlamydia-related complications.
['Igietseme|Joseph U|JU|', 'Omosun|Yusuf|Y|', 'Nagy|Tamas|T|', 'Stuchlik|Olga|O|', 'Reed|Matthew S|MS|', 'He|Qing|Q|', 'Partin|James|J|', 'Joseph|Kahaliah|K|', 'Ellerson|Debra|D|', 'George|Zenas|Z|', 'Goldstein|Jason|J|', 'Eko|Francis O|FO|', 'Bandea|Claudiu|C|', 'Pohl|Jan|J|', 'Black|Carolyn M|CM|']
D000199:Actins D000818:Animals D015820:Cadherins D002460:Cell Line D002689:Chlamydia D002690:Chlamydia Infections D003094:Collagen D055513:Connective Tissue Growth Factor D058750:Epithelial-Mesenchymal Transition D016326:Extracellular Matrix Proteins D005353:Fibronectins D005355:Fibrosis D051379:Mice D035683:MicroRNAs D058628:Myofibroblasts D050778:NFATC Transcription Factors D017346:Protein Serine-Threonine Kinases D011505:Protein-Tyrosine Kinases D000077293:Receptor, Transforming Growth Factor-beta Type I D018125:Receptors, Transforming Growth Factor beta D055760:SOXF Transcription Factors D016212:Transforming Growth Factor beta
Chlamydia fibrosis epithelial-mesenchymal transition (EMT) miRNAs myofibroblasts Chlamydia trachomatis extracellular matrix proteins