{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T20:56:12Z","timestamp":1788555372213,"version":"build-2803163510"},"reference-count":38,"publisher":"The Endocrine Society","issue":"4","license":[{"start":{"date-parts":[[2019,11,30]],"date-time":"2019-11-30T00:00:00Z","timestamp":1575072000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"name":"GEO Repository","award":["GSE136339"],"award-info":[{"award-number":["GSE136339"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Context<\/jats:title><jats:p>Hepatitis C virus (HCV) infection is a prevalent disease worldwide. Thyroid dysfunction is one of the most common extrahepatic manifestations of HCV infection. We hypothesized that HCV can directly infect human thyrocytes thereby causing thyroid dysfunction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Setting<\/jats:title><jats:p>Human thyrocytes in primary cell culture, ML-1 human thyroid cell line, and Huh7.5 human hepatocyte cell line were infected with HCV using the Huh7.5JFH1 cell line that releases infectious HCV virions. After infection, the release of new virions, production of proinflammatory cytokines, and expression of miR-122 were evaluated. Ribonucleic acid (RNA) extracted from HCV-infected cells and mock-infected cells was subjected to RNA sequencing and transcriptomic analysis. Ingenuity pathway analysis was used to detect up- and down-regulated pathways.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Human thyrocytes express major HCV entry factors including CD81, occludin, claudin-1, and scavenger receptor class B1. Viral infection of thyroid cells was confirmed by detection of HCV core protein in supernatants and negative-sense HCV RNA in cell lysates. HCV infection of thyrocytes induced the production of the chemokine CXCL-8 and the proinflammatory cytokines tumor necrosis factor alpha (TNF-\u03b1) and significantly increased the expression of miR-122. Moreover, HCV infection of thyrocytes decreased expression of the thyroid peroxidase and thyroglobulin genes and increased expression of the deiodinase 2 gene. The top upregulated pathways in HCV-infected thyrocytes were immune pathways and metabolic pathways, while infected hepatocytes upregulated lipid and glucose metabolism pathways as previously reported.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>HCV infection may induce thyroid dysfunction by different mechanisms including direct infection of thyrocytes leading to activation of inflammatory pathways and upregulation of miR-122. These findings support a general mechanism for viral induction of autoimmunity through direct infection of target tissues.<\/jats:p><\/jats:sec>","DOI":"10.1210\/clinem\/dgz241","type":"journal-article","created":{"date-parts":[[2019,12,2]],"date-time":"2019-12-02T12:12:34Z","timestamp":1575288754000},"page":"1157-1168","source":"Crossref","is-referenced-by-count":19,"title":["Hepatitis C Virus Infection of Human Thyrocytes: Metabolic, Hormonal, and Immunological Implications"],"prefix":"10.1210","volume":"105","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7619-8701","authenticated-orcid":false,"given":"Sara Salehi","family":"Hammerstad","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Oslo University Hospital, Ullev\u00e5l, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason T","family":"Blackard","sequence":"first","affiliation":[{"name":"Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Lombardi","sequence":"first","affiliation":[{"name":"Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randall P","family":"Owen","sequence":"first","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology Mount Sinai Hospital, Icahn School of Medicine New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erlinda","family":"Concepcion","sequence":"first","affiliation":[{"name":"Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengzi","family":"Yi","sequence":"first","affiliation":[{"name":"Department of Medicine Bioinformatics Core, Icahn School of Medicine at Mount Sinai, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijia","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Medicine Bioinformatics Core, Icahn School of Medicine at Mount Sinai, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1590-2547","authenticated-orcid":false,"given":"Yaron","family":"Tomer","sequence":"first","affiliation":[{"name":"Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2019,11,30]]},"reference":[{"issue":"3","key":"2020042119472197500_CIT0001","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1007\/s11904-015-0274-8","article-title":"Extrahepatic manifestations of hepatitis C infection: navigating CHASM","volume":"12","author":"Sherman","year":"2015","journal-title":"Curr HIV\/AIDS Rep."},{"issue":"1","key":"2020042119472197500_CIT0002","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/hep.21283","article-title":"Extrahepatic replication of HCV: insights into clinical manifestations and biological consequences","volume":"44","author":"Blackard","year":"2006","journal-title":"Hepatology."},{"issue":"12","key":"2020042119472197500_CIT0003","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1016\/j.autrev.2016.09.006","article-title":"International diagnostic guidelines for patients with HCV-related extrahepatic manifestations. 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