title: Bile Acids Act as Soluble Host Restriction Factors Limiting Cytomegalovirus Replication in Hepatocytes.
abstract: The liver constitutes a prime site of cytomegalovirus (CMV) replication and latency. Hepatocytes produce, secrete, and recycle a chemically diverse set of bile acids, with the result that interactions between bile acids and cytomegalovirus inevitably occur. Here we determined the impact of naturally occurring bile acids on mouse CMV (MCMV) replication. In primary mouse hepatocytes, physiological concentrations of taurochenodeoxycholic acid (TCDC), glycochenodeoxycholic acid, and to a lesser extent taurocholic acid significantly reduced MCMV-induced gene expression and diminished the generation of virus progeny, while several other bile acids did not exert antiviral effects. The anticytomegalovirus activity required active import of bile acids via the sodium-taurocholate-cotransporting polypeptide (NTCP) and was consistently observed in hepatocytes but not in fibroblasts. Under conditions in which alpha interferon (IFN-α) lacks antiviral activity, physiological TCDC concentrations were similarly effective as IFN-γ. A detailed investigation of distinct steps of the viral life cycle revealed that TCDC deregulates viral transcription and diminishes global translation in infected cells.
  
  
  
  Cytomegaloviruses are members of the Betaherpesvirinae subfamily. Primary infection leads to latency, from which cytomegaloviruses can reactivate under immunocompromised conditions and cause severe disease manifestations, including hepatitis. The present study describes an unanticipated antiviral activity of conjugated bile acids on MCMV replication in hepatocytes. Bile acids negatively influence viral transcription and exhibit a global effect on translation. Our data identify bile acids as site-specific soluble host restriction factors against MCMV, which may allow rational design of anticytomegalovirus drugs using bile acids as lead compounds.
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Anna-Kathrin
authors.initials: AK
authors.lastname: Schupp
authors.affiliation: Institute for Virology, Heinrich-Heine-University, Düsseldorf, Germany.|Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Mirko
authors.initials: M
authors.lastname: Trilling
authors.affiliation: Institute for Virology, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Rattay
authors.affiliation: Institute for Virology, Heinrich-Heine-University, Düsseldorf, Germany.|Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Vu Thuy Khanh
authors.initials: VTK
authors.lastname: Le-Trilling
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Haselow
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Stindt
authors.affiliation: Institute for Virology, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Albert
authors.initials: A
authors.lastname: Zimmermann
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Häussinger
authors.affiliation: Institute for Virology, Heinrich-Heine-University, Düsseldorf, Germany hartmut.hengel@uniklinik-freiburg.de Dirk.Graf@med.uni-duesseldorf.de.|Department for Medical Microbiology and Hygiene, Institute of Virology, Albert-Ludwigs-University, Freiburg, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Hengel
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Düsseldorf, Germany hartmut.hengel@uniklinik-freiburg.de Dirk.Graf@med.uni-duesseldorf.de.
authors.forename: Dirk
authors.initials: D
authors.lastname: Graf
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001647:Bile Acids and Salts / Q000494:pharmacology*; D003587:Cytomegalovirus / Q000472:pathogenicity*; D003586:Cytomegalovirus Infections / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D004261:DNA Replication / Q000187:drug effects; D004279:DNA, Viral / Q000235:genetics; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D029363:Organic Anion Transporters, Sodium-Dependent / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000502:physiology; D053633:Receptor, Interferon alpha-beta / Q000502:physiology; D027981:Symporters / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D001647:Bile Acids and Salts; D004279:DNA, Viral; C496283:Fxr1h protein, mouse; C508032:Ifnar1 protein, mouse; D029363:Organic Anion Transporters, Sodium-Dependent; D016601:RNA-Binding Proteins; D027981:Symporters; C071908:sodium-bile acid cotransporter; D053633:Receptor, Interferon alpha-beta