Solute Carrier NTCP Regulates Innate Antiviral Immune Responses Targeting Hepatitis C Virus Infection of Hepatocytes.

Eloi R. Verrier (1) , Che C. Colpitts (1) , Charlotte Bach (1) , Laura Heydmann (1) , Laetitia Zona (1) , Fei Xiao (1) , Christine Thumann (1) , Emilie Crouchet (1) , Raphaël Gaudin (1) , Camille Sureau (2) , Cosset François-Loïc (3, 4) , Jane A. Mckeating (5) , Patrick Pessaux (1, 6) , Yujin Hoshida (7) , Catherine Schuster (1) , Mirjam B. Zeisel (1) , Thomas F. Baumert (1, 6)

1 IVH - Institut de Recherche sur les Maladies Virales et Hépatiques
2 INTS, Laboratoire de Virologie Moléculaire, Paris, France
3 EVIR - Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy
4 LabEx ECOFECT Inserm U1111
5 University of Birmingham [Birmingham]
6 IHU Strasbourg - L'Institut hospitalo-universitaire de Strasbourg
7 MSSM - Icahn School of Medicine at Mount Sinai [New York]

Chronic hepatitis B, C, and D virus (HBV, HCV, and HDV) infections are the leading causes of liver disease and cancer worldwide. Recently, the solute carrier and sodium taurocholate co-transporter NTCP has been identified as a receptor for HBV and HDV. Here, we uncover NTCP as a host factor regulating HCV infection. Using gain- and loss-of-function studies, we show that NTCP mediates HCV infection of hepatocytes and is relevant for cell-to-cell transmission. NTCP regulates HCV infection by augmenting the bile-acid-mediated repression of interferon-stimulated genes (ISGs), including IFITM3. In conclusion, our results uncover NTCP as a mediator of innate antiviral immune responses in the liver, and they establish a role for NTCP in the infection process of multiple viruses via distinct mechanisms. Collectively, our findings suggest a role for solute carriers in the regulation of innate antiviral responses, and they have potential implications for virus-host interactions and antiviral therapies.

Mots clés: Interferons; NTCP; Organic Anion Transporters; innate immune responses; Innate; Biological Transport; Cell Line; Tumor; Gene Expression Regulation; Gene Silencing; Hepacivirus; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis C; hepatitis C virus; hepatitis D virus; Hepatitis Delta Virus; Hepatocytes; host factor; Humans; Immunity; Bile Acids and Salts; antiviral therapy; Antiviral Agents; Sodium-Dependent; Peptides; Protein Binding; Protein Precursors; signaling; solute carrier; Symporters; viral entry; Virus Internalization

Domaines: Médecine humaine et pathologie; Bactériologie; Virologie

Eloi R. Verrier, Che C. Colpitts, Charlotte Bach, Laura Heydmann, Laetitia Zona, et al.. Solute Carrier NTCP Regulates Innate Antiviral Immune Responses Targeting Hepatitis C Virus Infection of Hepatocytes.. Cell Reports, 2016, 17 (5), pp.1357-1368. ⟨10.1016/j.celrep.2016.09.084⟩. ⟨hal-01911211⟩