Project Description

TP09: Determinants of success and failure to control hepatitis C virus infection by the interferon system

A hallmark of hepatitis C virus (HCV) infections is the high propensity to establish persistence. This is achieved by active suppression and perturbation of both innate and adaptive immune responses. However the mechanistic details are still poorly understood and the relative contributions of the various immune escape strategies for persistence are unknown. Here we want to address how HCV activates the interferon (IFN) system via MDA5, study the role of IFN-λ polymorphisms in control of HCV, how nitric oxide contributes to suppression of HCV replication and determine the impact of long-term IFN exposure on HCV-specific cellular immunity.
Neufeldt CJ, Cortese M, Acosta EG, Bartenschlager R. 2018. Rewiring cellular networks by members of the Flaviviridae family. Nat Rev Microbiol.16(3):125-142. doi: 10.1038/nrmicro.2017.170.
Mutz P, Metz P, Lempp FA, Bender S, Qu B, Schöneweis K, Seitz S, Tu T, Restuccia A, Frankish J, Dächert C, Schusser B, Koschny R, Polychronidis G, Schemmer P, Hoffmann K, Baumert TF, Binder M, Urban S, Bartenschlager R. 2018. HBV Bypasses the Innate Immune Response and Does not Protect HCV From Antiviral Activity of Interferon. Gastroenterology. 2018 Jan 31. pii: S0016-5085(18)30112-4. doi: 10.1053/j.gastro.2018.01.044. (Epub ahead of print).
Pollmann J, Götz JJ, Rupp D, Strauss O, Granzin M, Grünvogel O, Mutz P, Kramer C, Lasitschka F, Lohmann V, Björkström NK, Thimme R, Bartenschlager R, Cerwenka A. 2017. Hepatitis C virus-induced natural killer cell proliferation involves monocyte-derived cells and the OX40/OX40L axis.J Hepatol. 2017 Oct 31. pii: S0168-8278(17)32400-5. doi: 10.1016/j.jhep.2017.10.021. [Epub ahead of print]
Kaufmann SHE, Dorhoi A, Hotchkiss RS, Bartenschlager R. 2017. Host-directed therapies for bacterial and viral infections. Nat Rev Drug Discov. 2017 Sep 22. doi: 10.1038/nrd.2017.162
Levander S, Holmström F, Frelin L, Ahlén G, Rupp D, Long G, Bartenschlager R, Sällberg M. 2017. Immune-mediated effects targeting hepatitis C virus in a syngeneic replicon cell transplantation mouse model. Gut. 2017 Jun 23. pii: gutjnl-2016-313579. doi: 10.1136/gutjnl-2016-313579. (Epub ahead of print)
Tu T, Bühler S, Bartenschlager R. 2017. Chronic viral hepatitis and its association with liver cancer. Biol Chem. 398(8):817-837. doi: 10.1515/hsz-2017-0118. Review.
Willemsen J, Wicht O, Wolanski JC, Baur N, Bastian S, Haas DA, Matula P, Knapp B, Meyniel-Schicklin L, Wang C, Bartenschlager R, Lohmann V, Rohr K, Erfle H, Kaderali L, Marcotrigiano J, Pichlmair A, Binder M. 2017. Phosphorylation-Dependent Feedback Inhibition of RIG-I by DAPK1 Identified by Kinome-wide siRNA Screening. Mol Cell. 65(3):403-415.e8. doi: 10.1016/j.molcel.2016.12.021.
Roth H, Magg V, Uch F, Mutz P, Klein P, Haneke K, Lohmann V, Bartenschlager R, Fackler OT, Locker N, Stoecklin G, Ruggieri A. 2017. Flavivirus Infection Uncouples Translation Suppression from Cellular Stress Responses. MBio. 8(1). pii: e02150-16. doi: 10.1128/mBio.02150-16. Erratum in: MBio. 2017 Apr 18;8(2).
Senís E, Mockenhaupt S, Rupp D, Bauer T, Paramasivam N, Knapp B, Gronych J, Grosse S, Windisch MP, Schmidt F, Theis FJ, Eils R, Lichter P, Schlesner M, Bartenschlager R, Grimm D. 2017. TALEN/CRISPR-mediated engineering of a promoterless anti-viral RNAi hairpin into an endogenous miRNA locus. Nucleic Acids Res. 45(1):e3. doi: 10.1093/nar/gkw805.
Bender S, Reuter A, Eberle F, Einhorn E, Binder M, Bartenschlager R. 2015. Activation of type I and III interferon response by mitochondrial and peroxisomal MAVS and inhibition by hepatitis C virus. PLoS Pathog. 11(11):e1005264. doi: 10.1371/journal.ppat.1005264.
Hiet MS, Bauhofer O, Zayas M, Roth H, Tanaka Y, Schirmacher P, Willemsen J, Grünvogel O, Bender S, Binder M, Lohmann V, Lotteau V, Ruggieri Bartenschlager R. 2015. Control of temporal activation of hepatitis C virus-induced interferon response by domain 2 of nonstructural protein 5A. J Hepatol 63:829-37. *co-corresponding authors
Seigel B, Bengsch B, Lohmann V, Bartenschlager R, Blum HE, Thimme R. 2013. Factors that determine the antiviral efficacy of HCV-specific CD8+ T cells ex vivo. Gastroenterology 144:426-36.
Pichlmair A, Kandasamy K, Alvisi G, Mulhern O, Sacco R, Habjan M, Binder M, Stefanovic A, Eberle CA, Goncalves A, Bürckstümmer T, Müller AC, Fauster A, Holze C, Lindsten K, Goodbourn S, Kochs G, We- ber F, Bartenschlager R, Bowie AG, Bennett KL, Colinge J, Superti-Furga G. 2012. Viral immune modu- lators perturb the human molecular network by common and unique strategies. Nature 487:486-90.
Metz P, Dazert E, Ruggieri A, Mazur J, Kaderali L, Kaul A, Zeuge U, Windisch MP, Trippler M, Lohmann V, Binder M, Frese M, Bartenschlager R. 2012. Identification of type I and type II interferon-induced ef- fectors controlling hepatitis C virus replication. Hepatology 56:2082-93.
Bauhofer O, Ruggieri A, Schmid B, Schirmacher P, Bartenschlager R. 2012. Persistence of HCV in qui- escent hepatic cells under conditions of an IFN-induced antiviral response. Gastroenterology 143:429-38.
Binder M, Eberle F, Seitz S, Mücke N, Hüber CM, Kiani N, Kaderali L, Lohmann V, Dalpke A, Barten- schlager R. 2011. Molecular mechanism of signal perception and integration by the innate immune sen- sor retinoic acid-inducible gene-I (RIG-I). J Biol Chem 286:27278-87.
Jo J, Aichele U, Kersting N, Klein R, Aichele P, Bisse E, Sewell AK, Blum HE, Bartenschlager R, Loh- mann V, Thimme R. 2009. Analysis of CD8+ T-cell-mediated inhibition of hepatitis C virus replication us- ing a novel immunological model. Gastroenterology 136:1391-401.
Dazert E, Neumann-Haefelin C, Bressanelli S, Fitzmaurice K, Kort J, Timm J, McKiernan S, Kelleher D, Gruener N, Tavis JE, Rosen HR, Shaw J, Bowness P, Blum HE, Klenerman P, Bartenschlager R*, Thimme R*. 2009. Loss of viral fitness and cross-recognition by CD8+ T cells limit HCV escape from a protective HLA-B27-restricted human immune response. J Clin Invest 119:376-86.* co-corresponding authors
Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, Bartenschlager R, Tschopp J. 2005. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437:1167-72