Hepatitis D Virus Infection of Mice Expressing Human Sodium Taurocholate Co-transporting Polypeptide

PLoS Pathog. 2015 Apr 22;11(4):e1004840. doi: 10.1371/journal.ppat.1004840. eCollection 2015 Apr.

Abstract

Hepatitis D virus (HDV) is the smallest virus known to infect human. About 15 million people worldwide are infected by HDV among those 240 million infected by its helper hepatitis B virus (HBV). Viral hepatitis D is considered as one of the most severe forms of human viral hepatitis. No specific antivirals are currently available to treat HDV infection and antivirals against HBV do not ameliorate hepatitis D. Liver sodium taurocholate co-transporting polypeptide (NTCP) was recently identified as a common entry receptor for HDV and HBV in cell cultures. Here we show HDV can infect mice expressing human NTCP (hNTCP-Tg). Antibodies against critical regions of HBV envelope proteins blocked HDV infection in the hNTCP-Tg mice. The infection was acute yet HDV genome replication occurred efficiently, evident by the presence of antigenome RNA and edited RNA species specifying large delta antigen in the livers of infected mice. The resolution of HDV infection appears not dependent on adaptive immune response, but might be facilitated by innate immunity. Liver RNA-seq analyses of HDV infected hNTCP-Tg and type I interferon receptor 1 (IFNα/βR1) null hNTCP-Tg mice indicated that in addition to induction of type I IFN response, HDV infection was also associated with up-regulation of novel cellular genes that may modulate HDV infection. Our work has thus proved the concept that NTCP is a functional receptor for HDV infection in vivo and established a convenient small animal model for investigation of HDV pathogenesis and evaluation of antiviral therapeutics against the early steps of infection for this important human pathogen.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Viral / pharmacology
  • Cells, Cultured
  • Crosses, Genetic
  • Female
  • Hepatitis D / drug therapy
  • Hepatitis D / metabolism*
  • Hepatitis D / pathology
  • Hepatitis D / virology
  • Hepatitis Delta Virus / drug effects
  • Hepatitis Delta Virus / immunology
  • Hepatitis Delta Virus / physiology*
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism*
  • Hepatocytes / pathology
  • Hepatocytes / virology
  • Host-Pathogen Interactions* / drug effects
  • Humans
  • Immunity, Innate / drug effects
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Organic Anion Transporters, Sodium-Dependent / genetics
  • Organic Anion Transporters, Sodium-Dependent / metabolism*
  • Receptor, Interferon alpha-beta / genetics
  • Receptor, Interferon alpha-beta / metabolism
  • Recombinant Fusion Proteins / metabolism
  • Specific Pathogen-Free Organisms
  • Symporters / genetics
  • Symporters / metabolism*
  • Viral Envelope Proteins / antagonists & inhibitors
  • Viral Envelope Proteins / metabolism

Substances

  • Antibodies, Monoclonal
  • Antibodies, Viral
  • Ifnar1 protein, mouse
  • Organic Anion Transporters, Sodium-Dependent
  • Recombinant Fusion Proteins
  • Symporters
  • Viral Envelope Proteins
  • sodium-bile acid cotransporter
  • Receptor, Interferon alpha-beta

Associated data

  • BioProject/PRJNA236433

Grant support

This work was funded by the National Science and Technology Major Project, China (2013ZX09509102), the Ministry of Science and Technology, China (2010CB530101,2011CB812501), and the Science and Technology Bureau of Beijing Municipal Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.