title: 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.affiliation: Graduate Program in Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; National Institute of Biological Sciences, Zhongguancun Life Science Park, Changping, Beijing, China.
authors.forename: Wenhui
authors.initials: W
authors.lastname: He
authors.affiliation: National Institute of Biological Sciences, Zhongguancun Life Science Park, Changping, Beijing, China.
authors.forename: Bijie
authors.initials: B
authors.lastname: Ren
authors.affiliation: National Institute of Biological Sciences, Zhongguancun Life Science Park, Changping, Beijing, China.
authors.forename: Fengfeng
authors.initials: F
authors.lastname: Mao
authors.affiliation: National Institute of Biological Sciences, Zhongguancun Life Science Park, Changping, Beijing, China.
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Jing
authors.affiliation: National Institute of Biological Sciences, Zhongguancun Life Science Park, Changping, Beijing, China.
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Li
authors.affiliation: National Institute of Biological Sciences, Zhongguancun Life Science Park, Changping, Beijing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: National Institute of Biological Sciences, Zhongguancun Life Science Park, Changping, Beijing, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Peng
authors.affiliation: National Institute of Biological Sciences, Zhongguancun Life Science Park, Changping, Beijing, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Yan
authors.affiliation: National Institute of Biological Sciences, Zhongguancun Life Science Park, Changping, Beijing, China; Graduate School of Beijing Normal University, Beijing, China.
authors.forename: Yonghe
authors.initials: Y
authors.lastname: Qi
authors.affiliation: National Institute of Biological Sciences, Zhongguancun Life Science Park, Changping, Beijing, China.
authors.forename: Yinyan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Drexel Institute for Biotechnology and Virology Research, Drexel University College of Medicine, Doylestown, Pennsylvania, United States of America.
authors.forename: Ju-Tao
authors.initials: JT
authors.lastname: Guo
authors.affiliation: National Institute of Biological Sciences, Zhongguancun Life Science Park, Changping, Beijing, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Sui
authors.affiliation: National Institute of Biological Sciences, Zhongguancun Life Science Park, Changping, Beijing, China.
authors.forename: Fengchao
authors.initials: F
authors.lastname: Wang
authors.affiliation: Graduate Program in Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; National Institute of Biological Sciences, Zhongguancun Life Science Park, Changping, Beijing, China.
authors.forename: Wenhui
authors.initials: W
authors.lastname: Li
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000914:Antibodies, Viral / Q000494:pharmacology; D002478:Cells, Cultured; D003433:Crosses, Genetic; D005260:Female; D003699:Hepatitis D / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D003698:Hepatitis Delta Virus / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics / Q000378:metabolism*; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D014759:Viral Envelope Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; C508032:Ifnar1 protein, mouse; D029363:Organic Anion Transporters, Sodium-Dependent; D011993:Recombinant Fusion Proteins; D027981:Symporters; D014759:Viral Envelope Proteins; C071908:sodium-bile acid cotransporter; D053633:Receptor, Interferon alpha-beta