title: Hepatitis-C-virus-induced microRNAs dampen interferon-mediated antiviral signaling.
abstract: Hepatitis C virus (HCV) infects 200 million people globally, and 60-80% of cases persist as a chronic infection that will progress to cirrhosis and liver cancer in 2-10% of patients. We recently demonstrated that HCV induces aberrant expression of two host microRNAs (miRNAs), miR-208b and miR-499a-5p, encoded by myosin genes in infected hepatocytes. These miRNAs, along with AU-rich-element-mediated decay, suppress IFNL2 and IFNL3, members of the type III interferon (IFN) gene family, to support viral persistence. In this study, we show that miR-208b and miR-499a-5p also dampen type I IFN signaling in HCV-infected hepatocytes by directly down-regulating expression of the type I IFN receptor chain, IFNAR1. Inhibition of these miRNAs by using miRNA inhibitors during HCV infection increased expression of IFNAR1. Additionally, inhibition rescued the antiviral response to exogenous type I IFN, as measured by a marked increase in IFN-stimulated genes and a decrease in HCV load. Treatment of HCV-infected hepatocytes with type I IFN increased expression of myosins over HCV infection alone. Since these miRNAs can suppress type III IFN family members, these data collectively define a novel cross-regulation between type I and III IFNs during HCV infection.
authors.affiliation: Department of Immunology, University of Washington, Seattle, Washington, USA.
authors.forename: Abigail
authors.initials: A
authors.lastname: Jarret
authors.affiliation: Department of Immunology, University of Washington, Seattle, Washington, USA.
authors.forename: Adelle P
authors.initials: AP
authors.lastname: McFarland
authors.affiliation: Department of Immunology, University of Washington, Seattle, Washington, USA.
authors.forename: Stacy M
authors.initials: SM
authors.lastname: Horner
authors.affiliation: Department of Immunology, University of Washington, Seattle, Washington, USA.
authors.forename: Alison
authors.initials: A
authors.lastname: Kell
authors.affiliation: Department of Immunology, University of Washington, Seattle, Washington, USA.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schwerk
authors.affiliation: Department of Immunology, University of Washington, Seattle, Washington, USA.
authors.forename: MeeAe
authors.initials: M
authors.lastname: Hong
authors.affiliation: Department of Immunology, University of Washington, Seattle, Washington, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Badil
authors.affiliation: Department of Immunology, University of Washington, Seattle, Washington, USA.
authors.forename: Rochelle C
authors.initials: RC
authors.lastname: Joslyn
authors.affiliation: Biogen-Idec Inc., Cambridge, Massachusetts, USA.
authors.forename: Darren P
authors.initials: DP
authors.lastname: Baker
authors.affiliation: Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research-Frederick, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.|Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Carrington
authors.affiliation: Department of Medicine and Genetics Program, University of Arkansas for Medical Sciences, and The Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA.
authors.forename: Curt H
authors.initials: CH
authors.lastname: Hagedorn
authors.affiliation: Department of Immunology, University of Washington, Seattle, Washington, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Gale
authors.affiliation: Department of Immunology, University of Washington, Seattle, Washington, USA.
authors.forename: Ram
authors.initials: R
authors.lastname: Savan
mesh_terms: D064113:CRISPR-Cas Systems; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000276:immunology*; D055786:Gene Knockout Techniques; D056945:Hep G2 Cells; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology; D019698:Hepatitis C, Chronic / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology*; D006801:Humans; D007370:Interferon Type I / Q000276:immunology*; D007372:Interferons; D007378:Interleukins / Q000276:immunology; D035683:MicroRNAs / Q000276:immunology*; D009218:Myosins / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D000095022:Interferon Lambda
chemical_list: D007370:Interferon Type I; D007372:Interferons; D007378:Interleukins; D035683:MicroRNAs; D009218:Myosins; D053633:Receptor, Interferon alpha-beta; C507964:IFNAR1 protein, human; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C550906:MIRN208 microRNA, human; C548683:MIRN499 microRNA, human