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

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.

• Authors: Wenhui He, Bijie Ren, Fengfeng Mao, Zhiyi Jing, Yunfei Li, Yang Liu, Bo Peng, Huan Yan, Yonghe Qi, Yinyan Sun, Ju-Tao Guo, Jianhua Sui, Fengchao Wang, Wenhui Li
• Journal: PLoS pathogens (PLoS Pathog) Vol. 11 Issue 4 Pg. e1004840 (Apr 2015) ISSN: 1553-7374 [Electronic] United States
• PMID: 25902143 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Animals
• Antibodies, Monoclonal (pharmacology)
• Antibodies, Viral (pharmacology)
• Cells, Cultured
• Crosses, Genetic
• Female
• Hepatitis D (drug therapy, metabolism, pathology, virology)
• Hepatitis Delta Virus (drug effects, immunology, physiology)
• Hepatocytes (drug effects, metabolism, pathology, 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, metabolism)
• Receptor, Interferon alpha-beta (genetics, metabolism)
• Recombinant Fusion Proteins (metabolism)
• Specific Pathogen-Free Organisms
• Symporters (genetics, metabolism)
• Viral Envelope Proteins (antagonists & inhibitors, metabolism)