Hepatitis C virus infection induces autocrine interferon signaling by human liver endothelial cells and release of exosomes, which inhibits viral replication

Silvia Giugliano, Michael Kriss, Lucy Golden-Mason, Evgenia Dobrinskikh, Amy E.L. Stone, Alejandro Soto-Gutierrez, Angela Mitchell, Salman R. Khetani, Daisuke Yamane, Mark Stoddard, Hui Li, George M. Shaw, Michael G. Edwards, Stanley M. Lemon, Michael Gale, Vijay H. Shah, Hugo R. Rosen

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

Background & Aims Liver sinusoidal endothelial cells (LSECs) make up a large proportion of the nonparenchymal cells in the liver. LSECs are involved in induction of immune tolerance, but little is known about their functions during hepatitis C virus (HCV) infection. Methods Primary human LSECs (HLSECs) and immortalized liver endothelial cells (TMNK-1) were exposed to various forms of HCV, including full-length transmitted/founder virus, sucrose-purified Japanese fulminant hepatitis-1 (JFH-1), a virus encoding a luciferase reporter, and the HCV-specific pathogen-associated molecular pattern molecules. Cells were analyzed by confocal immunofluorescence, immunohistochemical, and polymerase chain reaction assays. Results HLSECs internalized HCV, independent of cell-cell contacts; HCV RNA was translated but not replicated. Through pattern recognition receptors (Toll-like receptor 7 and retinoic acid-inducible gene 1), HCV RNA induced consistent and broad transcription of multiple interferons (IFNs); supernatants from primary HLSECs transfected with HCV-specific pathogen-associated molecular pattern molecules increased induction of IFNs and IFN-stimulated genes in HLSECs. Recombinant type I and type III IFNs strongly up-regulated HLSEC transcription of IFN λ3 (IFNL3) and viperin (RSAD2), which inhibit replication of HCV. Compared with CD8+ T cells, HLSECs suppressed HCV replication within Huh7.5.1 cells, also inducing IFN-stimulated genes in co-culture. Conditioned media from IFN-stimulated HLSECs induced expression of antiviral genes by uninfected primary human hepatocytes. Exosomes, derived from HLSECs after stimulation with either type I or type III IFNs, controlled HCV replication in a dose-dependent manner. Conclusions Cultured HLSECs produce factors that mediate immunity against HCV. HLSECs induce self-amplifying IFN-mediated responses and release of exosomes with antiviral activity.

Original languageEnglish (US)
Pages (from-to)392-402.e13
JournalGastroenterology
Volume148
Issue number2
DOIs
StatePublished - Feb 1 2015

Keywords

  • Cytokine
  • Immune Regulation
  • Innate Immunity
  • Toll-Like Receptor

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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    Giugliano, S., Kriss, M., Golden-Mason, L., Dobrinskikh, E., Stone, A. E. L., Soto-Gutierrez, A., Mitchell, A., Khetani, S. R., Yamane, D., Stoddard, M., Li, H., Shaw, G. M., Edwards, M. G., Lemon, S. M., Gale, M., Shah, V. H., & Rosen, H. R. (2015). Hepatitis C virus infection induces autocrine interferon signaling by human liver endothelial cells and release of exosomes, which inhibits viral replication. Gastroenterology, 148(2), 392-402.e13. https://doi.org/10.1053/j.gastro.2014.10.040