title: Hepatitis E Virus Infects Neurons and Brains.
abstract: Hepatitis E virus (HEV), as a hepatotropic virus, is supposed to exclusively infect the liver and only cause hepatitis. However, a broad range of extrahepatic manifestations (in particular, idiopathic neurological disorders) have been recently reported in association with its infection. In this study, we have demonstrated that various human neural cell lines (embryonic stem cell-derived neural lineage cells) induced pluripotent stem cell-derived human neurons and primary mouse neurons are highly susceptible to HEV infection. Treatment with interferon-α or ribavirin, the off-label antiviral drugs for chronic hepatitis E, exerted potent antiviral activities against HEV infection in neural cells. More importantly, in mice and monkey peripherally inoculated with HEV particles, viral RNA and protein were detected in brain tissues. Finally, patients with HEV-associated neurological disorders shed the virus into cerebrospinal fluid, indicating a direct infection of their nervous system. Thus, HEV is neurotropic in vitro, and in mice, monkeys, and possibly humans. These results challenge the dogma of HEV as a pure hepatotropic virus and suggest that HEV infection should be considered in the differential diagnosis of idiopathic neurological disorders.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Xinying
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Medical Faculty, Kunming University of Science and Technology, China.
authors.forename: Fen
authors.initials: F
authors.lastname: Huang
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.affiliation: Departments of Neuroscience, and.
authors.forename: Zhanmin
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Psychiatry, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Femke M S
authors.initials: FMS
authors.lastname: de Vrij
authors.affiliation: Psychiatry, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Ane C
authors.initials: AC
authors.lastname: Ayo-Martin
authors.affiliation: Psychiatry, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: van der Kroeg
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Manzhi
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Yuebang
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Wenshi
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Wanlu
authors.initials: W
authors.lastname: Cao
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Yijin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Psychiatry, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Kushner
authors.affiliation: Service d'Hépato-Gastro-Entérologie, Hopital Purpan, and.|Université Paul Sabatier, Toulouse, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Marie Peron
authors.affiliation: Université Paul Sabatier, Toulouse, France.|MR 152 IRD-Toulouse 3 University, France Internal Medicine, Digestive Department, Purpan, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Alric
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Robert A
authors.initials: RA
authors.lastname: de Man
authors.affiliation: Departments of Neurology, and.|Immunology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Bart C
authors.initials: BC
authors.lastname: Jacobs
authors.affiliation: Department of Neurology, Jeroen Bosch Ziekenhuis, 's-Hertogenbosch.
authors.forename: Jeroen J
authors.initials: JJ
authors.lastname: van Eijk
authors.affiliation: Department of (Neuro)Pathology, Academisch Medisch Centrum, Amsterdam-Zuidoost, and.
authors.forename: Eleonora M A
authors.initials: EMA
authors.lastname: Aronica
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Dave
authors.initials: D
authors.lastname: Sprengers
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Herold J
authors.initials: HJ
authors.lastname: Metselaar
authors.affiliation: Departments of Neuroscience, and.|Netherlands Institute for Neuroscience, Royal Dutch Academy for Arts and Science, Amsterdam.
authors.forename: Chris I
authors.initials: CI
authors.lastname: de Zeeuw
authors.affiliation: Royal Cornwall Hospital, and.|European Centre for Environment & Human Health, University of Exeter, Truro, United Kingdom.
authors.forename: Harry R
authors.initials: HR
authors.lastname: Dalton
authors.affiliation: MR 152 IRD-Toulouse 3 University, France Internal Medicine, Digestive Department, Purpan, France.|Department of Nephrology and Organ Transplantation, CHU Rangueil, and.|INSERM U1043, IFR-BMT, CHU Purpan, Toulouse, France.
authors.forename: Nassim
authors.initials: N
authors.lastname: Kamar
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Maikel P
authors.initials: MP
authors.lastname: Peppelenbosch
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Qiuwei
authors.initials: Q
authors.lastname: Pan
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D001921:Brain / Q000473:pathology / Q000821:virology*; D045744:Cell Line, Tumor; D002555:Cerebrospinal Fluid / Q000821:virology; D005260:Female; D020275:Guillain-Barre Syndrome / Q000821:virology; D016751:Hepatitis E / Q000188:drug therapy / Q000473:pathology*; D016752:Hepatitis E virus / Q000472:pathogenicity*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D008099:Liver / Q000473:pathology / Q000821:virology; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009474:Neurons / Q000473:pathology / Q000821:virology*; D012367:RNA, Viral / Q000032:analysis; D012254:Ribavirin / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects; D017201:Virus Shedding
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D012367:RNA, Viral; D012254:Ribavirin
keywords: central nervous system; cerebrospinal fluid; hepatitis E virus; peripheral nervous system.