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J Clin Endocrinol Metab. 2019 Nov 30. pii: dgz241. doi: 10.1210/clinem/dgz241. [Epub ahead of print]

Hepatitis C virus infection of human thyrocytes: metabolic, hormonal, and immunological implications.

Author information

1
Department of Pediatrics, Oslo University Hospital, Ullevål, Oslo, Norway.
2
Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH.
3
Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY.
4
Department of Surgery, Division of Surgical Oncology Mount Sinai Hospital, Icahn School of Medicine New York, NY.
5
Department of Medicine Bioinformatics Core, Icahn School of Medicine at Mount Sinai, New York, NY.

Abstract

CONTEXT:

Hepatitis C virus (HCV) infection is a prevalent disease worldwide. Thyroid dysfunction is one of the most common extrahepatic manifestation of HCV infection. We hypothesized that HCV can directly infect human thyrocytes thereby causing thyroid dysfunction.

SETTING:

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 pro-inflammatory cytokines, and expression of miR-122 were evaluated. RNA extracted from HCV-infected cells and mock-infected cells were subjected to RNA sequencing and transcriptomic analysis. Ingenuity pathway analysis was used to detect up- and down-regulated pathways.

RESULTS:

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 pro-inflammatory cytokines TNFα 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.

CONCLUSIONS:

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.

KEYWORDS:

Cytokine; Hepatitis C virus; IL-8; RNA Sequencing; Thyroiditis Autoimmune; miR-122

PMID:
31784757
DOI:
10.1210/clinem/dgz241

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