Project Description

TP11: Global effects on host cell signalling by continuous stimulation of innate antiviral responses in persistent viral infections

Virus infection triggers pathogen recognition receptors, which will activate several antiviral effector pathways. This is a dynamic and transient process that typically ceases concomitant with a reduction of the pathogen-derived stimulus, ultimately reestablishing resting-state homeostasis. The situation is different in persistent infections, such as Hepatitis C, B or D virus infection, where permanent presence of viral compounds continuously stimulates antiviral pathways, leading to a perturbed, infected-state homeostasis. With state-of-the-art MS technology, this project will characterize the molecular alterations of the cellular signaling network during infected-state homeostasis, and establish their functional consequences for innate, but also adaptive immune responses to chronic hepatitis viruses.
Namineni S, O'Connor T, Faure-Dupuy S, Johansen P, Riedl T, Liu K, Xu H, Singh I, Shinde P, Li F, Pandyra A, Sharma P, Ringelhan M, Muschaweckh A, Borst K, Blank P, Lampl S, Durantel D, Farhat R, Weber A, Lenggenhager D, Kündig TM, Staeheli P, Protzer U, Wohlleber D, Holzmann B, Binder M, Breuhahn K, Assmus LM, Nattermann J, Abdullah Z, Rolland M, Dejardin E, Lang PA, Lang KS, Karin M, Lucifora J, Kalinke U, Knolle PA, Heikenwalder M. 2020. A dual role for hepatocyte-intrinsic canonical NF-κB signaling in virus control. J Hepatol. 2020 Jan 15. pii: S0168-8278(20)30010-6. doi: 10.1016/j.jhep.2019.12.019. (Epub ahead of print)
Gebhardt A, Bergant V, Schnepf D, Moser M, Meiler A, Togbe D, Mackowiak C, Reinert LS, Paludan SR, Ryffel B, Stukalov A, Staeheli P, Pichlmair A. 2019. The alternative cap-binding complex is required for antiviral defense in vivo.PLoS Pathog. 2019 Dec 19;15(12):e1008155.
Płaszczyca A, Scaturro P, Neufeldt CJ, Cortese M, Cerikan B, Ferla S, Brancale A, Pichlmair A, Bartenschlager R. 2019. A novel interaction between dengue virus nonstructural protein 1 and the NS4A-2K-4B precursor is required for viral RNA replication but not for formation of the membranous replication organelle. PLoS Pathog. 15(5):e1007736
Cadena C, Ahmad S, Xavier A, Willemsen J, Park S, Park JW, Oh SW, Fujita T, Hou F, Binder M, Hur S. 2019. Ubiquitin-Dependent and -Independent Roles of E3 Ligase RIPLET in Innate Immunity. Cell. 177(5):1187-1200.e16. doi: 10.1016/j.cell.2019.03.017.
Scaturro P, Pichlmair A. 2019. Oxeiptosis: a discreet way to respond to radicals. Curr Opin Immunol. 2019 Feb;56:37-43. doi: 10.1016/j.coi.2018.10.006.
Hubel P, Urban C, Bergant V, Schneider WM, Knauer B, Stukalov A, Scaturro P, Mann A, Brunotte L, Hoffmann HH, Schoggins JW, Schwemmle M, Mann M, Rice CM, Pichlmair A. 2019. A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape. Nat Immunol. 2019 Mar 4. doi: 10.1038/s41590-019-0323-3. (Epub ahead of print)
Scaturro P, Stukalov A, Haas DA, Cortese M, Draganova K, Płaszczyca A, Bartenschlager R, Götz M, Pichlmair A. 2018. An orthogonal proteomic survey uncovers novel Zika virus host factors. Nature. 561(7722):253-257. doi: 10.1038/s41586-018-0484-5.
Haas DA, Meiler A, Geiger K, Vogt C, Preuss E, Kochs G, Pichlmair A. 2018. Viral targeting of TFIIB impairs de novo polymerase II recruitment and affects antiviral immunity. PLoS Pathog 14(4):e1006980. doi: 10.1371/journal.ppat.1006980. eCollection 2018 Apr.
Grünvogel O, Colasanti O, Lee JY, Klöss V, Belouzard S, Reustle A, Esser-Nobis K, Hesebeck-Brinckmann J, Mutz P, Hoffmann K, Mehrabi A, Koschny R, Vondran FWR, Gotthardt D, Schnitzler P, Neumann-Haefelin C, Thimme R, Binder M, Bartenschlager R, Dubuisson J, Dalpke AH, Lohmann V. Secretion of Hepatitis C Virus Replication Intermediates Reduces Activation of Toll-Like Receptor 3 in Hepatocytes. Gastroenterology. 2018 Jun;154(8):2237-2251.e16. doi: 10.1053/j.gastro.2018.03.020.
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. 154(6):1791-1804. doi: 10.1053/j.gastro.2018.01.044.
Holze C, Michaudel C, Mackowiak C, Haas D. A, Benda C, Hubel P, Pennemann F. L, Schnepf, D, Wettmarshausen J, Braun M, Leung D.W, Amarasinghe G. K, Perocchi F, Staeheli P, Ryffel B, Pichlmair A. 2018. Oxeiptosis, a ROS-induced caspase-independent apoptosis-like cell-death pathway. Nature Immunol. 19: 130–140. doi:10.1038/s41590-017-0013-y
Goonawardane N, Gebhardt A, Bartlett C, Pichlmair A, Harris M. 2017. Phosphorylation of serine 225 in hepatitis C virus NS5A regulates protein-protein interactions. J Virol. 91(17). pii: e00805-17. doi: 10.1128/JVI.00805-17
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.
Binder M, …, Bartenschlager R, Lohmann V, Kaderali L. 2013. Replication Vesicles are Load- and Choke Points in the Hepatitis C Virus Lifecycle. PLoS Pathog 9: e1003561.
Pichlmair A, .., Binder M, …, Bartenschlager R, …, Superti-Furga G. 2012. Viral immune modulators perturb the human molecular network by common and unique strategies. Nature 487: 486–490.
Metz P, ..., Ruggieri A, …, Lohmann V, Binder M, ..., Bartenschlager R. 2012. Identification of type I and type II interferon-induced effectors controlling hepatitis C virus replication. Hepatology 56: 2082-93.
Binder M, …, Lohmann V, Bartenschlager R. 2011. Molecular mechanism of signal perception and integration by the innate immune sensor retinoic acid-inducible gene-I (RIG-I). J Biol Chem 286: 27278–27287.
Pichlmair A, …, Superti-Furga G. 2011 IFIT1 is an antiviral protein that recognizes 5’-triphosphate RNA. Nat Immunol 12:624-30.
Schulz O, Pichlmair A, …, Reis e Sousa C. 2010. Protein kinase R contributes to immunity against specific viruses by regulating interferon mRNA integrity. Cell Host Microbe 7:354-61.
Binder M, Kochs G, Bartenschlager R, Lohmann V. 2007. Hepatitis C virus escape from the interferon regulato- ry factor 3 pathway by a passive and active evasion strategy. Hepatology 46: 1365–1374.
Pichlmair A, ..., Reis e Sousa C. 2006. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5'- phosphates. Science 314: 997–1001.
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