Role of Epithelial-Mesenchyme Transition in Chlamydia Pathogenesis
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 c...
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| Veröffentlicht in: | PloS one 2015-12, Vol.10 (12), p.e0145198-e0145198 |
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| creator | Igietseme, Joseph U Omosun, Yusuf Stuchlik, Olga Reed, Matthew S Partin, James He, Qing Joseph, Kahaliah Ellerson, Debra Bollweg, Brigid George, Zenas Eko, Francis O Bandea, Claudiu Liu, Hsi Yang, Genyan Shieh, Wun-Ju Pohl, Jan Karem, Kevin Black, Carolyn M |
| description | 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. |
| doi_str_mv | 10.1371/journal.pone.0145198 |
| format | Article |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0145198</identifier><identifier>PMID: 26681200</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Bacteria ; Cadherins - genetics ; Cadherins - metabolism ; Caspase inhibitors ; Caspases - metabolism ; Cell activation ; Cervix ; Chlamydia ; Chlamydia Infections - metabolism ; Chlamydia Infections - pathology ; Chlamydia trachomatis ; Complications ; Complications and side effects ; Connexin 43 ; Deactivation ; Development and progression ; Disease control ; Ductile-brittle transition ; E-cadherin ; Epithelial cells ; Epithelial-Mesenchymal Transition ; Epithelium ; Female ; Fertility ; Fibronectin ; Fibronectins - genetics ; Fibronectins - metabolism ; Fibrosis ; Fracture mechanics ; Gelatinase B ; HeLa Cells ; Homeobox ; Homeodomain Proteins - genetics ; Homeodomain Proteins - metabolism ; Human papillomavirus ; Humans ; Immunohistochemistry ; Inactivation ; Infertility ; Kruppel-Like Transcription Factors - genetics ; Kruppel-Like Transcription Factors - metabolism ; Lymphocytes T ; Markers ; Matrix Metalloproteinase 9 - genetics ; Matrix Metalloproteinase 9 - metabolism ; Mesenchyme ; Mice ; Mice, Inbred C57BL ; MicroRNAs - genetics ; miRNA ; Papillomavirus infections ; Pathogenesis ; Patient outcomes ; Protein binding ; Proteins ; Proteomics ; Regulators ; Ribonucleic acid ; Risk factors ; RNA ; Rodents ; Sexually transmitted diseases ; Signaling ; Snail Family Transcription Factors ; STD ; T-cadherin ; Thrombospondin 1 - genetics ; Thrombospondin 1 - metabolism ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Tumor necrosis factor ; Tumor Necrosis Factor-alpha - metabolism ; Tumor necrosis factor-α ; Tumorigenesis ; Viruses ; Zinc ; Zinc Finger E-box-Binding Homeobox 1 ; Zinc finger proteins</subject><ispartof>PloS one, 2015-12, Vol.10 (12), p.e0145198-e0145198</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication: https://creativecommons.org/publicdomain/zero/1.0/ (the “License”) Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-d504aea753f8790dfde7dc4e162eb5f13e4da7dfc85b1df44eb58a6cbd48dcaa3</citedby><cites>FETCH-LOGICAL-c692t-d504aea753f8790dfde7dc4e162eb5f13e4da7dfc85b1df44eb58a6cbd48dcaa3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683008/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683008/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23847,27903,27904,53769,53771,79346,79347</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26681200$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Seshu, J.</contributor><creatorcontrib>Igietseme, Joseph U</creatorcontrib><creatorcontrib>Omosun, Yusuf</creatorcontrib><creatorcontrib>Stuchlik, Olga</creatorcontrib><creatorcontrib>Reed, Matthew S</creatorcontrib><creatorcontrib>Partin, James</creatorcontrib><creatorcontrib>He, Qing</creatorcontrib><creatorcontrib>Joseph, Kahaliah</creatorcontrib><creatorcontrib>Ellerson, Debra</creatorcontrib><creatorcontrib>Bollweg, Brigid</creatorcontrib><creatorcontrib>George, Zenas</creatorcontrib><creatorcontrib>Eko, Francis O</creatorcontrib><creatorcontrib>Bandea, Claudiu</creatorcontrib><creatorcontrib>Liu, Hsi</creatorcontrib><creatorcontrib>Yang, Genyan</creatorcontrib><creatorcontrib>Shieh, Wun-Ju</creatorcontrib><creatorcontrib>Pohl, Jan</creatorcontrib><creatorcontrib>Karem, Kevin</creatorcontrib><creatorcontrib>Black, Carolyn M</creatorcontrib><title>Role of Epithelial-Mesenchyme Transition in Chlamydia Pathogenesis</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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.</description><subject>Animals</subject><subject>Bacteria</subject><subject>Cadherins - genetics</subject><subject>Cadherins - metabolism</subject><subject>Caspase inhibitors</subject><subject>Caspases - metabolism</subject><subject>Cell activation</subject><subject>Cervix</subject><subject>Chlamydia</subject><subject>Chlamydia Infections - metabolism</subject><subject>Chlamydia Infections - pathology</subject><subject>Chlamydia trachomatis</subject><subject>Complications</subject><subject>Complications and side effects</subject><subject>Connexin 43</subject><subject>Deactivation</subject><subject>Development and progression</subject><subject>Disease control</subject><subject>Ductile-brittle transition</subject><subject>E-cadherin</subject><subject>Epithelial cells</subject><subject>Epithelial-Mesenchymal Transition</subject><subject>Epithelium</subject><subject>Female</subject><subject>Fertility</subject><subject>Fibronectin</subject><subject>Fibronectins - genetics</subject><subject>Fibronectins - metabolism</subject><subject>Fibrosis</subject><subject>Fracture mechanics</subject><subject>Gelatinase B</subject><subject>HeLa Cells</subject><subject>Homeobox</subject><subject>Homeodomain Proteins - genetics</subject><subject>Homeodomain Proteins - metabolism</subject><subject>Human papillomavirus</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Inactivation</subject><subject>Infertility</subject><subject>Kruppel-Like Transcription Factors - genetics</subject><subject>Kruppel-Like Transcription Factors - metabolism</subject><subject>Lymphocytes T</subject><subject>Markers</subject><subject>Matrix Metalloproteinase 9 - genetics</subject><subject>Matrix Metalloproteinase 9 - metabolism</subject><subject>Mesenchyme</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>MicroRNAs - genetics</subject><subject>miRNA</subject><subject>Papillomavirus infections</subject><subject>Pathogenesis</subject><subject>Patient outcomes</subject><subject>Protein binding</subject><subject>Proteins</subject><subject>Proteomics</subject><subject>Regulators</subject><subject>Ribonucleic acid</subject><subject>Risk factors</subject><subject>RNA</subject><subject>Rodents</subject><subject>Sexually transmitted diseases</subject><subject>Signaling</subject><subject>Snail Family Transcription Factors</subject><subject>STD</subject><subject>T-cadherin</subject><subject>Thrombospondin 1 - genetics</subject><subject>Thrombospondin 1 - metabolism</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><subject>Tumor necrosis factor</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><subject>Tumor necrosis factor-α</subject><subject>Tumorigenesis</subject><subject>Viruses</subject><subject>Zinc</subject><subject>Zinc Finger E-box-Binding Homeobox 1</subject><subject>Zinc finger proteins</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNklGL1DAQx4so3nn6DUQLgujDrkmTJu2LcC6nLpycnKevIU0m2yxpszatuN_e1O0dW7kHyUPC5Df_yUz-SfIcoyUmHL_b-qFrpVvufAtLhGmOy-JBcopLki1YhsjDo_NJ8iSELUI5KRh7nJxkjBU4Q-g0-XDtHaTepBc729fgrHSLLxCgVfW-gfSmk22wvfVtatt0VTvZ7LWV6VfZ134DLQQbniaPjHQBnk37WfL948XN6vPi8urTenV-uVCszPqFzhGVIHlOTMFLpI0GrhUFzDKocoMJUC25NqrIK6wNpTFaSKYqTQutpCRnycuD7s75IKb2g8CcliWLKmUk1gdCe7kVu842stsLL634G_DdRsiut8qBAJIXNCO5QriiuCLS8IpRwk3OM8W4jlrvp2pD1YBW0PaddDPR-U1ra7HxvwRlBUGoiAJvJoHO_xwg9KKxQYFzsgU_jO-OAyE5L1BEX_2D3t_dRG1kbMC2xse6ahQV5_HlPM9pNmot76Hi0tBYFb1ibIzPEt7OEiLTw-9-I4cQxPrb9f-zVz_m7Osjtgbp-jp4N4xmCnOQHkDV-RA6MHdDxkiMVr-dhhitLiarx7QXxx90l3TrbfIHGcH5Ow</recordid><startdate>20151217</startdate><enddate>20151217</enddate><creator>Igietseme, Joseph U</creator><creator>Omosun, Yusuf</creator><creator>Stuchlik, Olga</creator><creator>Reed, Matthew S</creator><creator>Partin, James</creator><creator>He, Qing</creator><creator>Joseph, Kahaliah</creator><creator>Ellerson, Debra</creator><creator>Bollweg, Brigid</creator><creator>George, Zenas</creator><creator>Eko, Francis O</creator><creator>Bandea, Claudiu</creator><creator>Liu, Hsi</creator><creator>Yang, Genyan</creator><creator>Shieh, Wun-Ju</creator><creator>Pohl, Jan</creator><creator>Karem, Kevin</creator><creator>Black, Carolyn M</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20151217</creationdate><title>Role of Epithelial-Mesenchyme Transition in Chlamydia Pathogenesis</title><author>Igietseme, Joseph U ; Omosun, Yusuf ; Stuchlik, Olga ; Reed, Matthew S ; Partin, James ; He, Qing ; Joseph, Kahaliah ; Ellerson, Debra ; Bollweg, Brigid ; George, Zenas ; Eko, Francis O ; Bandea, Claudiu ; Liu, Hsi ; Yang, Genyan ; Shieh, Wun-Ju ; Pohl, Jan ; Karem, Kevin ; Black, Carolyn M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-d504aea753f8790dfde7dc4e162eb5f13e4da7dfc85b1df44eb58a6cbd48dcaa3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animals</topic><topic>Bacteria</topic><topic>Cadherins - genetics</topic><topic>Cadherins - metabolism</topic><topic>Caspase inhibitors</topic><topic>Caspases - metabolism</topic><topic>Cell activation</topic><topic>Cervix</topic><topic>Chlamydia</topic><topic>Chlamydia Infections - metabolism</topic><topic>Chlamydia Infections - pathology</topic><topic>Chlamydia trachomatis</topic><topic>Complications</topic><topic>Complications and side effects</topic><topic>Connexin 43</topic><topic>Deactivation</topic><topic>Development and progression</topic><topic>Disease control</topic><topic>Ductile-brittle transition</topic><topic>E-cadherin</topic><topic>Epithelial cells</topic><topic>Epithelial-Mesenchymal Transition</topic><topic>Epithelium</topic><topic>Female</topic><topic>Fertility</topic><topic>Fibronectin</topic><topic>Fibronectins - genetics</topic><topic>Fibronectins - metabolism</topic><topic>Fibrosis</topic><topic>Fracture mechanics</topic><topic>Gelatinase B</topic><topic>HeLa Cells</topic><topic>Homeobox</topic><topic>Homeodomain Proteins - genetics</topic><topic>Homeodomain Proteins - metabolism</topic><topic>Human papillomavirus</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Inactivation</topic><topic>Infertility</topic><topic>Kruppel-Like Transcription Factors - genetics</topic><topic>Kruppel-Like Transcription Factors - metabolism</topic><topic>Lymphocytes T</topic><topic>Markers</topic><topic>Matrix Metalloproteinase 9 - genetics</topic><topic>Matrix Metalloproteinase 9 - metabolism</topic><topic>Mesenchyme</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>MicroRNAs - genetics</topic><topic>miRNA</topic><topic>Papillomavirus infections</topic><topic>Pathogenesis</topic><topic>Patient outcomes</topic><topic>Protein binding</topic><topic>Proteins</topic><topic>Proteomics</topic><topic>Regulators</topic><topic>Ribonucleic acid</topic><topic>Risk factors</topic><topic>RNA</topic><topic>Rodents</topic><topic>Sexually transmitted diseases</topic><topic>Signaling</topic><topic>Snail Family Transcription Factors</topic><topic>STD</topic><topic>T-cadherin</topic><topic>Thrombospondin 1 - genetics</topic><topic>Thrombospondin 1 - metabolism</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><topic>Tumor necrosis factor</topic><topic>Tumor Necrosis Factor-alpha - metabolism</topic><topic>Tumor necrosis factor-α</topic><topic>Tumorigenesis</topic><topic>Viruses</topic><topic>Zinc</topic><topic>Zinc Finger E-box-Binding Homeobox 1</topic><topic>Zinc finger proteins</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Igietseme, Joseph U</creatorcontrib><creatorcontrib>Omosun, Yusuf</creatorcontrib><creatorcontrib>Stuchlik, Olga</creatorcontrib><creatorcontrib>Reed, Matthew S</creatorcontrib><creatorcontrib>Partin, James</creatorcontrib><creatorcontrib>He, Qing</creatorcontrib><creatorcontrib>Joseph, Kahaliah</creatorcontrib><creatorcontrib>Ellerson, Debra</creatorcontrib><creatorcontrib>Bollweg, Brigid</creatorcontrib><creatorcontrib>George, Zenas</creatorcontrib><creatorcontrib>Eko, Francis O</creatorcontrib><creatorcontrib>Bandea, Claudiu</creatorcontrib><creatorcontrib>Liu, Hsi</creatorcontrib><creatorcontrib>Yang, Genyan</creatorcontrib><creatorcontrib>Shieh, Wun-Ju</creatorcontrib><creatorcontrib>Pohl, Jan</creatorcontrib><creatorcontrib>Karem, Kevin</creatorcontrib><creatorcontrib>Black, Carolyn M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Igietseme, Joseph U</au><au>Omosun, Yusuf</au><au>Stuchlik, Olga</au><au>Reed, Matthew S</au><au>Partin, James</au><au>He, Qing</au><au>Joseph, Kahaliah</au><au>Ellerson, Debra</au><au>Bollweg, Brigid</au><au>George, Zenas</au><au>Eko, Francis O</au><au>Bandea, Claudiu</au><au>Liu, Hsi</au><au>Yang, Genyan</au><au>Shieh, Wun-Ju</au><au>Pohl, Jan</au><au>Karem, Kevin</au><au>Black, Carolyn M</au><au>Seshu, J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Role of Epithelial-Mesenchyme Transition in Chlamydia Pathogenesis</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-12-17</date><risdate>2015</risdate><volume>10</volume><issue>12</issue><spage>e0145198</spage><epage>e0145198</epage><pages>e0145198-e0145198</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26681200</pmid><doi>10.1371/journal.pone.0145198</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2015-12, Vol.10 (12), p.e0145198-e0145198 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1749961629 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Animals Bacteria Cadherins - genetics Cadherins - metabolism Caspase inhibitors Caspases - metabolism Cell activation Cervix Chlamydia Chlamydia Infections - metabolism Chlamydia Infections - pathology Chlamydia trachomatis Complications Complications and side effects Connexin 43 Deactivation Development and progression Disease control Ductile-brittle transition E-cadherin Epithelial cells Epithelial-Mesenchymal Transition Epithelium Female Fertility Fibronectin Fibronectins - genetics Fibronectins - metabolism Fibrosis Fracture mechanics Gelatinase B HeLa Cells Homeobox Homeodomain Proteins - genetics Homeodomain Proteins - metabolism Human papillomavirus Humans Immunohistochemistry Inactivation Infertility Kruppel-Like Transcription Factors - genetics Kruppel-Like Transcription Factors - metabolism Lymphocytes T Markers Matrix Metalloproteinase 9 - genetics Matrix Metalloproteinase 9 - metabolism Mesenchyme Mice Mice, Inbred C57BL MicroRNAs - genetics miRNA Papillomavirus infections Pathogenesis Patient outcomes Protein binding Proteins Proteomics Regulators Ribonucleic acid Risk factors RNA Rodents Sexually transmitted diseases Signaling Snail Family Transcription Factors STD T-cadherin Thrombospondin 1 - genetics Thrombospondin 1 - metabolism Transcription Factors - genetics Transcription Factors - metabolism Tumor necrosis factor Tumor Necrosis Factor-alpha - metabolism Tumor necrosis factor-α Tumorigenesis Viruses Zinc Zinc Finger E-box-Binding Homeobox 1 Zinc finger proteins |
| title | Role of Epithelial-Mesenchyme Transition in Chlamydia Pathogenesis |
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