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Hepatitis D Virus Infection of Mice Expressing Human Sodium Taurocholate Co-transporting Polypeptide
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
PLOS
Published: April 22, 2015
DOI: 10.1371/journal.ppat.1004840
Wenhui He, Wenhui Li
Graduate Program in Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Wenhui He, Bijie Ren, Fengfeng Mao, Zhiyi Jing, Yunfei Li, Yang Liu, Bo Peng, Huan Yan, Yonghe Qi, Yinyan Sun, Jianhua Sui, Fengchao Wang, Wenhui Li
National Institute of Biological Sciences, Zhongguancun Life Science Park, Changping, Beijing, China
Yonghe Qi
Graduate School of Beijing Normal University, Beijing, China
Ju-Tao Guo
Drexel Institute for Biotechnology and Virology Research, Drexel University College of Medicine, Doylestown, Pennsylvania, United States of America
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.
Author Summary
Currently 15 million people worldwide are infected by hepatitis D virus (HDV). HDV is the smallest virus known to infect human. With co-infection of its helper hepatitis B virus (HBV), viral hepatitis D is considered as the most severe form of viral hepatitis. No specific anti-HDV drugs are available; antivirals against HBV do not ameliorate hepatitis D. We report mice expressing a human bile acids transporter sodium taurocholate co-transporting polypeptide (NTCP) in the liver support HDV infection, providing a useful model for studying antivirals against HDV and understanding how the simplest virus interacts with a host in vivo. Our transcriptome analyses of livers of infected mice have unveiled interaction landscape of HDV and the hosts, laying a foundation for further studies.
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发表于 2015-4-25 14:17