Project Description

TP08: Mechanisms of interferon induction by hepatitis D virus and impact of chronic innate immune activation on antiviral immunity

Chronic virus infections can mediate persistent activation of the innate immune system and result in a dysfunctional immune response. The activation of interferon signaling in chronic viral hepatitis correlates with more severe disease, but also with a favorable prognosis of organ acceptance in the setting of liver transplantation. The aim of this project is to establish models of chronic HDV infection that induces innate immunity by yet poorly understood mechanisms. We will define the innate sensing and signaling pathways that are engaged upon HDV infection and decipher the functional consequences of chronic innate immune activation on cellular immunity in vitro and in vivo.
Dargel C, Bassani-Sternberg M, Hasreiter J, Zani F, Bockmann JH, Thiele F, Bohne F, Wisskirchen K, Wilde S, Sprinzl MF, Schendel DJ, Krackhardt AM, Uckert W, Wohlleber D, Schiemann M, Stemmer K, Heikenwälder M, Busch DH, Richter G, Mann M, Protzer U. 2015. T cells engineered to express a T-cell receptor specific for Glypican recognize and kill hepatoma cells in vitro and in mice. Gastroenterology S0016-5085(15)00782-9.
Bohne F, Londono MC, Benitez C, Miquel R, Martinez-Llordella M, Russo C, Ortiz C, Bonaccorsi-Riani E, Brander C, Bauer T, Protzer U, Jaeckel E, Taubert R, Forns X, Navasa M, Berenguer M, Rimola A, Loza- no JJ, Sanchez-Fueyo A. 2014. HCV-induced immune responses influence the development of opera- tional tolerance after liver transplantation in humans. Sci Transl Med 6: 242ra281.
Bohne F, Martinez-Llordella M, Lozano JJ, Miquel R, Benitez C, Londono MC, Manzia TM, Angelico, R, Swinkels DW, Tjalsma H, Bonaccorsi-Riani Jaeckel E, Taubert R, Pirenne J, Rimola A, Tisone G, Sanchez-Fueyo A. 2012. Intra-graft expression of genes involved in iron homeostasis predicts the devel- opment of operational tolerance in human liver transplantation. J Clin Invest 122: 368-382.
Krebs K, Bottinger N, Huang LR, Chmielewski M, Arzberger S, Gasteiger G, Jager C, Schmitt E, Bohne F, Aichler M, Uckert W, Abken H, Heikenwalder M, Knolle P, Protzer U. 2013. T cells expressing a chi- meric antigen receptor that binds hepatitis B virus envelope proteins control virus replication in mice. Gastroenterology 145: 456-465.
Bohne F, Chmielewski M, Ebert G, Wiegmann K, Kurschner T, Schulze A, Urban S, Kronke M, Abken, H, Protzer U. 2008. T cells redirected against hepatitis B virus surface proteins eliminate infected hepato- cytes. Gastroenterology 134: 239-247.
Ablasser A, Schmid-Burgk JL, Hemmerling I, Horvath GL, Schmidt T, Latz E, Hornung V. 2013. Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP. Nature 503: 530-534.
Ablasser A, Goldeck M, Cavlar T, Deimling T, Witte G, Rohl I, Hopfner KP, Ludwig J, Hornung V. 2013. cGAS produces a 2'-5'-linked cyclic dinucleotide second messenger that activates STING Nature 498: 380-384.
Ablasser A, Bauernfeind F, Hartmann G, Latz E, Fitzgerald KA*, Hornung V*. 2009. RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III-transcribed RNA intermediate. Nat Immunology 10: 1065-1072.* co-corresponding authors
Hornung V, Ellegast J, Kim S, Brzozka K, Jung A, Kato H, Poeck H, Akira S, Conzelmann KK, Schlee M, Endres S, Hartmann G. 2006. 5'-Triphosphate RNA is the ligand for RIG-I. Science 314: 994-997.
Hornung V, Guenthner-Biller M, Bourquin C, Ablasser A, Schlee M, Uematsu S, Noronha A, Manoharan M, Akira S, de Fougerolles A, Endres S, Hartmann G. 2005. Sequence-specific potent induction of IFN- alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nat Med 11: 263-270.