title: Role of Epithelial-Mesenchyme Transition in Chlamydia Pathogenesis.
abstract: Chlamydia trachomatis genital infection in women causes serious adverse reproductive complications, and is a strong co-factor for human papilloma virus (HPV)-associated cervical epithelial carcinoma. We tested the hypothesis that Chlamydia induces epithelial-mesenchyme transition (EMT) involving T cell-derived TNF-alpha signaling, caspase activation, cleavage inactivation of dicer and dysregulation of micro-RNA (miRNA) in the reproductive epithelium; the pathologic process of EMT causes fibrosis and fertility-related epithelial dysfunction, and also provides the co-factor function for HPV-related cervical epithelial carcinoma. Using a combination of microarrays, immunohistochemistry and proteomics, we showed that chlamydia altered the expression of crucial miRNAs that control EMT, fibrosis and tumorigenesis; specifically, miR-15a, miR-29b, miR-382 and MiR-429 that maintain epithelial integrity were down-regulated, while miR-9, mi-R-19a, miR-22 and miR-205 that promote EMT, fibrosis and tumorigenesis were up-regulated. Chlamydia induced EMT in vitro and in vivo, marked by the suppression of normal epithelial cell markers especially E-cadherin but up-regulation of mesenchymal markers of pathological EMT, including T-cadherin, MMP9, and fibronectin. Also, Chlamydia upregulated pro-EMT regulators, including the zinc finger E-box binding homeobox protein, ZEB1, Snail1/2, and thrombospondin1 (Thbs1), but down-regulated anti-EMT and fertility promoting proteins (i.e., the major gap junction protein connexin 43 (Cx43), Mets1, Add1Scarb1 and MARCKSL1). T cell-derived TNF-alpha signaling was required for chlamydial-induced infertility and caspase inhibitors prevented both infertility and EMT. Thus, chlamydial-induced T cell-derived TNF-alpha activated caspases that inactivated dicer, causing alteration in the expression of reproductive epithelial miRNAs and induction of EMT. EMT causes epithelial malfunction, fibrosis, infertility, and the enhancement of tumorigenesis of HPV oncogene-transformed epithelial cells. These findings provide a novel understanding of the molecular pathogenesis of chlamydia-associated diseases, which may guide a rational prevention strategy.
authors.affiliation: National Center for Emerging Zoonotic and Infectious Diseases, Centers for Disease Control & Prevention (CDC) Atlanta, GA 30333 United States of America.|Department of Microbiology, Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, GA 30310 United States of America.
authors.forename: Joseph U
authors.initials: JU
authors.lastname: Igietseme
authors.affiliation: National Center for Emerging Zoonotic and Infectious Diseases, Centers for Disease Control & Prevention (CDC) Atlanta, GA 30333 United States of America.|Department of Microbiology, Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, GA 30310 United States of America.
authors.forename: Yusuf
authors.initials: Y
authors.lastname: Omosun
authors.affiliation: National Center for Emerging Zoonotic and Infectious Diseases, Centers for Disease Control & Prevention (CDC) Atlanta, GA 30333 United States of America.
authors.forename: Olga
authors.initials: O
authors.lastname: Stuchlik
authors.affiliation: National Center for Emerging Zoonotic and Infectious Diseases, Centers for Disease Control & Prevention (CDC) Atlanta, GA 30333 United States of America.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Reed
authors.affiliation: National Center for Emerging Zoonotic and Infectious Diseases, Centers for Disease Control & Prevention (CDC) Atlanta, GA 30333 United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Partin
authors.affiliation: National Center for Emerging Zoonotic and Infectious Diseases, Centers for Disease Control & Prevention (CDC) Atlanta, GA 30333 United States of America.|Department of Microbiology, Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, GA 30310 United States of America.
authors.forename: Qing
authors.initials: Q
authors.lastname: He
authors.affiliation: National Center for Emerging Zoonotic and Infectious Diseases, Centers for Disease Control & Prevention (CDC) Atlanta, GA 30333 United States of America.
authors.forename: Kahaliah
authors.initials: K
authors.lastname: Joseph
authors.affiliation: National Center for Emerging Zoonotic and Infectious Diseases, Centers for Disease Control & Prevention (CDC) Atlanta, GA 30333 United States of America.
authors.forename: Debra
authors.initials: D
authors.lastname: Ellerson
authors.affiliation: National Center for Emerging Zoonotic and Infectious Diseases, Centers for Disease Control & Prevention (CDC) Atlanta, GA 30333 United States of America.
authors.forename: Brigid
authors.initials: B
authors.lastname: Bollweg
authors.affiliation: National Center for Emerging Zoonotic and Infectious Diseases, Centers for Disease Control & Prevention (CDC) Atlanta, GA 30333 United States of America.
authors.forename: Zenas
authors.initials: Z
authors.lastname: George
authors.affiliation: Department of Microbiology, Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, GA 30310 United States of America.
authors.forename: Francis O
authors.initials: FO
authors.lastname: Eko
authors.affiliation: National Center for Emerging Zoonotic and Infectious Diseases, Centers for Disease Control & Prevention (CDC) Atlanta, GA 30333 United States of America.
authors.forename: Claudiu
authors.initials: C
authors.lastname: Bandea
authors.affiliation: National Center for Emerging Zoonotic and Infectious Diseases, Centers for Disease Control & Prevention (CDC) Atlanta, GA 30333 United States of America.
authors.forename: Hsi
authors.initials: H
authors.lastname: Liu
authors.affiliation: National Center for Emerging Zoonotic and Infectious Diseases, Centers for Disease Control & Prevention (CDC) Atlanta, GA 30333 United States of America.
authors.forename: Genyan
authors.initials: G
authors.lastname: Yang
authors.affiliation: National Center for Emerging Zoonotic and Infectious Diseases, Centers for Disease Control & Prevention (CDC) Atlanta, GA 30333 United States of America.
authors.forename: Wun-Ju
authors.initials: WJ
authors.lastname: Shieh
authors.affiliation: National Center for Emerging Zoonotic and Infectious Diseases, Centers for Disease Control & Prevention (CDC) Atlanta, GA 30333 United States of America.
authors.forename: Jan
authors.initials: J
authors.lastname: Pohl
authors.affiliation: National Center for Emerging Zoonotic and Infectious Diseases, Centers for Disease Control & Prevention (CDC) Atlanta, GA 30333 United States of America.
authors.forename: Kevin
authors.initials: K
authors.lastname: Karem
authors.affiliation: National Center for Emerging Zoonotic and Infectious Diseases, Centers for Disease Control & Prevention (CDC) Atlanta, GA 30333 United States of America.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Black
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002690:Chlamydia Infections / Q000378:metabolism* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics; D000071250:Snail Family Transcription Factors; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D015820:Cadherins; D005353:Fibronectins; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D035683:MicroRNAs; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D019700:Thrombospondin 1; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C519422:ZEB1 protein, mouse; D000071799:Zinc Finger E-box-Binding Homeobox 1; D020169:Caspases; D020780:Matrix Metalloproteinase 9