title: Hepatitis C Virus Stimulates Murine CD8α-Like Dendritic Cells to Produce Type I Interferon in a TRIF-Dependent Manner.
abstract: Hepatitis C virus (HCV) induces interferon (IFN) stimulated genes in the liver despite of distinct innate immune evasion mechanisms, suggesting that beyond HCV infected cells other cell types contribute to innate immune activation. Upon coculture with HCV replicating cells, human CD141+ myeloid dendritic cells (DC) produce type III IFN, whereas plasmacytoid dendritic cells (pDC) mount type I IFN responses. Due to limitations in the genetic manipulation of primary human DCs, we explored HCV mediated stimulation of murine DC subsets. Coculture of HCV RNA transfected human or murine hepatoma cells with murine bone marrow-derived DC cultures revealed that only Flt3-L DC cultures, but not GM-CSF DC cultures responded with IFN production. Cells transfected with full length or subgenomic viral RNA stimulated IFN release indicating that infectious virus particle formation is not essential in this process. Use of differentiated DC from mice with genetic lesions in innate immune signalling showed that IFN secretion by HCV-stimulated murine DC was independent of MyD88 and CARDIF, but dependent on TRIF and IFNAR signalling. Separating Flt3-L DC cultures into pDC and conventional CD11b-like and CD8α-like DC revealed that the CD8α-like DC, homologous to the human CD141+ DC, release interferon upon stimulation by HCV replicating cells. In contrast, the other cell types and in particular the pDC did not. Injection of human HCV subgenomic replicon cells into IFN-β reporter mice confirmed the interferon induction upon HCV replication in vivo. These results indicate that HCV-replicating cells stimulate IFN secretion from murine CD8α-like DC independent of infectious virus production. Thus, this work defines basic principles of viral recognition by murine DC populations. Moreover, this model should be useful to explore the interaction between dendritic cells during HCV replication and to define how viral signatures are delivered to and recognized by immune cells to trigger IFN release.
authors.affiliation: Institute for Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Pfaender
authors.affiliation: Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Grabski
authors.affiliation: Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
authors.forename: Claudia N
authors.initials: CN
authors.lastname: Detje
authors.affiliation: Institute for Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Riebesehl
authors.affiliation: Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.|Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.|Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Lienenklaus
authors.affiliation: Institute for Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany.
authors.forename: Eike
authors.initials: E
authors.lastname: Steinmann
authors.affiliation: Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kalinke
authors.affiliation: Institute for Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pietschmann
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology*; D000818:Animals; D016827:CD8 Antigens / Q000276:immunology*; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology; D006801:Humans; D007370:Interferon Type I / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016827:CD8 Antigens; D007370:Interferon Type I; C431698:CD8alpha antigen; C476286:Ticam1 protein, mouse