Hepatitis-C-virus-induced microRNAs dampen interferon-mediated antiviral signaling.
Journal Article (Journal Article)
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.
Full Text
Duke Authors
Cited Authors
- Jarret, A; McFarland, AP; Horner, SM; Kell, A; Schwerk, J; Hong, M; Badil, S; Joslyn, RC; Baker, DP; Carrington, M; Hagedorn, CH; Gale, M; Savan, R
Published Date
- December 2016
Published In
Volume / Issue
- 22 / 12
Start / End Page
- 1475 - 1481
PubMed ID
- 27841874
Pubmed Central ID
- PMC5551900
Electronic International Standard Serial Number (EISSN)
- 1546-170X
Digital Object Identifier (DOI)
- 10.1038/nm.4211
Language
- eng
Conference Location
- United States