title: Uropathogenic Escherichia coli causes fibrotic remodelling of the epididymis.
abstract: Despite antibiotic treatment, up to 40% of patients have impaired fertility after epididymitis due to serovars of Escherichia coli, a frequent pathogen. The reasons for infertility are unclear, but it may result from epididymal duct obstruction. To determine whether E. coli infection of the epididymis causes obstruction due to fibrosis, and to identify the key mediators, tissues from patients with epididymitis were assessed. Additionally, epididymitis was induced with uropathogenic E. coli (UPEC) or commensal serovars in wild-type and MyD88(-/-) mice, which are relatively unresponsive to bacterial pathogens. Epididymal organ cultures were treated with activin A and bacteria and their histology and levels of cytokines and fibrosis markers were analysed. Patients with epididymitis showed severe fibrosis of the epididymal duct. In mice, UPEC infection also caused fibrosis and ductal obstruction in the cauda epididymis. Levels of mRNA for fibrotic markers (α-smooth muscle actin, fibronectin) and cytokines (activin A, TNFα, IL-1α, IL-1β, IL-6) and total collagen levels were significantly elevated. This fibrotic response was blunted by the loss of MyD88. Activin A induced fibrosis in cultured epididymis, which was inhibited by the activin-binding protein follistatin. In summary, bacterial epididymitis causes fibrosis and obstruction. The milder tissue damage in Myd88(-/-) UPEC epididymitis highlights the importance of the host response to infection in causing epididymal damage. Elevated levels of activin A in vivo and fibrotic remodelling elicited by activin A in vitro indicate that this cytokine is a potential target for supplementary treatment to antibiotic therapy. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Institute of Anatomy and Cell Biology, Justus-Liebig-University Giessen, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Michel
authors.affiliation: Centre of Reproductive Medicine and Andrology, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, People's Republic of China.
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Duan
authors.affiliation: Institute of Anatomy and Cell Biology, Justus-Liebig-University Giessen, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Stoschek
authors.affiliation: Institute of Anatomy and Cell Biology, Justus-Liebig-University Giessen, Germany.
authors.forename: Sudhanshu
authors.initials: S
authors.lastname: Bhushan
authors.affiliation: Institute of Anatomy and Cell Biology, Justus-Liebig-University Giessen, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Middendorff
authors.affiliation: Hudson Institute of Medical Research, Melbourne, Victoria, Australia.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Young
authors.affiliation: Department of Molecular and Translational Sciences, Monash University, Melbourne, Victoria, Australia.|Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia.|Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria, Australia.
authors.forename: Kate L
authors.initials: KL
authors.lastname: Loveland
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia.|Hudson Institute of Medical Research, Melbourne, Victoria, Australia.
authors.forename: David M De
authors.initials: DM
authors.lastname: Kretser
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia.|Hudson Institute of Medical Research, Melbourne, Victoria, Australia.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Hedger
authors.affiliation: Institute of Anatomy and Cell Biology, Justus-Liebig-University Giessen, Germany.|Department of Molecular and Translational Sciences, Monash University, Melbourne, Victoria, Australia.|Hudson Institute of Medical Research, Melbourne, Victoria, Australia.
authors.forename: Andreas
authors.initials: A
authors.lastname: Meinhardt
mesh_terms: D000199:Actins / Q000378:metabolism; D000368:Aged; D000818:Animals; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004822:Epididymis / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D004823:Epididymitis / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D004927:Escherichia coli Infections / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009130:Muscle, Smooth / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D056689:Uropathogenic Escherichia coli
chemical_list: D000199:Actins; D016207:Cytokines; D005353:Fibronectins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D003094:Collagen
keywords: activin A; epididymis; epididymitis; fibrosis; infection; uropathogenic Escherichia coli