Disturbance of the nuclear and nucleolar compartments by a viral interferon antagonist

Prof. Dr. Friedemann Weber

Institute for Virology
Philipps-University Marburg
Hans-Meerwein-Str. 2
D-35043 Marburg
Germany

Phone: ++49 6421 286 4525
Fax: ++49 6421 286 8962

Email : friedemann.weber@staff.uni-marburg.de
Homepage : http://www.uni-marburg.de/fb20/virologie/forschung/researchviro/ag-weber/index_html

Project description

Viruses have to cope with the antiviral type I interferon response, an essential and rapidly reacting component of the innate immune system. The binding of viral RNA to specific pathogen recognition receptors induces a signalling chain which eventually results in the activation of the genes for type I interferons (IFN-alpha and beta). IFNs are secreted cytokines which trigger a cascade of antiviral factors and activities in their target cells. Moreover, IFNs are shaping the subsequent, slower-reacting adaptive immune responses. In order to establish infection, viruses evolved a wide range of countermeasures to inhibit or modulate the induction, signalling, or action of the IFN system.

La Crosse virus (LACV; family Bunyaviridae) is a negative-strand RNA virus causing severe encephalitis in children. We have previously shown that the NSs protein of LACV is a strong inhibitor of the IFN system. NSs is thereby directly blocking the induction of the IFN genes by triggering the proteasomal degradation of RNA polymerase II (RNAP II), thus causing a rapid shut down of the host cell mRNA synthesis. Interestingly, NSs selectively targets the large subunit (RPB1) of transcriptionally active RNAP II complexes. This NSs phenotype has remarkable similarities to the DNA damage response (DDR).

Our research project B13 aims at elucidating the molecular mechanism of the virulence factor NSs. We hypothesize that NSs is taking advantage of the so far incompletely characterized DDR machinery to efficiently and rapidly shut down the antiviral host response. The specific goals of the project are

- to identify cellular interaction partners and map the relevant domains

- to investigate the involvement of the ubiquitin/proteasome system

- to fully characterize the NSs- and LACV-triggered cellular responses

- to investigate the contribution of the DDR machinery to the NSs action

Staff

Larissa Spiegelberg (PhD Student)
Andreas Schön (PhD Student)
Jörg Schmidt (Technical Assistant)

Selected publications since 2007

Original papers 

1. CERVANTES-BARRAGAN, L., R. ZÜST, F. WEBER, M. SPIEGEL, K. S. LANG, S. AKIRA, V. THIEL, B. LUDEWIG (2007): Control of coronavirus infection through plasmacytoid dendritic cell-derived type I interferon. Blood 109: 1131-1137

2. BLAKQORI, G., S. DELHAYE, M. HABJAN, C. D. BLAIR, I. SÁNCHEZ-VARGAS, K. E. OLSON, G. ATTARZADEH-YAZDI, R. FRAGKOUDIS, A. KOHL, U. KALINKE, S. WEISS, T. MICHIELS, P. STAEHELI, F. WEBER (2007): La Crosse Bunyavirus Nonstructural Protein NSs Serves to Suppress the Type I Interferon System of Mammalian Hosts. J. Virol. 81:4991-4999

3. ZÜST, R., L. CERVANTES-BARRAGAN, T. KURI, G. BLAKQORI, F. WEBER, B. LUDEWIG, V. THIEL (2007): Identification of Coronavirus Non-Structural Protein 1 as a Major Pathogenicity Factor – Implications for the Rational Design of Live Attenuated Coronavirus Vaccines. PLoS Pathogens 3 e109:1062-1072

4. HABJAN, M., I. ANDERSSON, J. KLINGSTRÖM, M. SCHÜMANN, A. MARTIN, P. ZIMMERMANN, V. WAGNER, A. PICHLMAIR, U. SCHNEIDER, E. MÜHLBERGER, A. MIRAZIMI, F. WEBER (2008): Processing of genome 5’ termini as a strategy of negative-strand RNA viruses to avoid RIG-I-dependent interferon induction. PLoS ONE 3 e2032: 1-8

5. HABJAN, M., N. PENSKI, M. SPIEGEL, F. WEBER (2008): T7 RNA polymerase-dependent and -independent systems for cDNA-based rescue of Rift Valley fever virus J. Gen. Virol. 89: 2157 – 2166

6. HABJAN, M., N. PENSKI, V. WAGNER, M. SPIEGEL, A. K. ÖVERBY, G. KOCHS, J. T. HUISKONEN, F. WEBER (2009): Efficient Production of Rift Valley Fever Virus-Like Particles: the Antiviral Protein MxA Can Inhibit Primary Transcription of Bunyaviruses. Virology 385:400-408

7. NÄSLUND, J., N. LAGERQVIST, M. HABJAN, Å. LUNDKVIST, M.  EVANDER, C. AHLM, F. WEBER*, G. BUCHT* (2009): Vaccination with virus-like particles protects mice from lethal infection of Rift Valley Fever Virus. Virology 385:409-415

8. HUISKONEN, J.T., A. K. ÖVERBY, F.  WEBER, K. GRÜNEWALD (2009): Electron Cryo-Microscopy and Single-Particle Averaging of Rift Valley Fever Virus: Evidence for Gn-Gc Glycoprotein Heterodimers. J. Virol. 83:3762-3769

9. HABJAN, M., A. PICHLMAIR, R. M. ELLIOTT, A. K. ÖVERBY, T. GLATTER, M. GSTAIGER, G. SUPERTI-FURGA, H. UNGER, F. WEBER (2009): NSs protein of Rift Valley Fever Virus induces the specific degradation of the double-stranded RNA-dependent protein kinase. J. Virol. 83:4365-4375

10. KURI, T., X. ZHANG, M. HABJAN, L. MARTÍNEZ-SOBRIDO, A. GARCÍA-SASTRE, Z. YUAN, F. WEBER (2009): Interferon priming enables cells to partially overturn the SARS-Coronavirus-induced block in innate immune activation. J. Gen. Virol. 90: 2686 - 2694

11. PICHLMAIR, A., M. HABJAN, H. UNGER, F. WEBER (2010): Virus-like particles expressing the nucleocapsid gene as an efficient vaccine against Rift Valley fever virus. Vector-Borne and Zoonotic Diseases 10:701-703

12. KURI, T., M. HABJAN, N. PENSKI, F. WEBER (2010): Species-independent bioassay for sensitive quantification of antiviral type I interferons. Virology Journal 7:50

13. ÖVERBY, A.K., V. L. POPOV, M. NIEDRIG, F. WEBER (2010): Tick-borne encephalitis virus delays interferon induction and hides its double-stranded RNA in intracellular membrane vesicles. J. Virol. 84:8470-8483

14. REGUERA, J., F. WEBER, S. CUSACK (2010): Bunyaviridae RNA polymerases (L-protein) have an N-terminal, influenza-like endonuclease domain, essential for viral cap-dependent transcription. PLoS Pathogens 6: e1001101

15. VERBRUGGEN P., M. RUF, G. BLAKQORI, A.K. OEVERBY, M. HEIDEMANN, D. EICK, F. WEBER (2011): Interferon antagonist NSs of La Crosse virus triggers a DNA-damage response-like degradation of transcribing RNA polymerase II. J. Biol. Chem. 286:3681-3692

16. WANG, H., A. VAHERI, F. WEBER, A. PLYUSNIN (2011): Old World hantaviruses do not produce detectable amounts of dsRNA in infected cells and the 5'-termini of their genomic RNAs are monophosphorylated. J. Gen. Virol. 92:1199-1204

17. FRENTZEN, A., K. HÜGING, J. BITZEGEIO, M. FRIESLAND, S. HAID, J. GENTZSCH, M. HOFFMANN, D. LINDEMANN, G. ZIMMER, F. ZIELECKI, F. WEBER, E. STEINMANN, T. PIETSCHMANN (2011): Completion of Hepatitis C Virus Replication Cycle in Heterokaryons Excludes Dominant Restrictions in Human Non-liver and Mouse Liver Cell Lines. PLoS Pathogens 7(4): e1002029

18. KURI, T., K. K. ERIKSSON, A. PUTICS, R. ZÜST, E. J. SNIJDER, A. D. DAVIDSON, S. G. SIDDELL, V. THIEL, J. ZIEBUHR, F. WEBER (2011): The ADP-ribose-1”-monophosphatase domains of SARS-coronavirus and Human coronavirus 229E mediate resistance to antiviral interferon responses. J. Gen. Virol. 92:1899-1905

19. Pichlmair, A., C. Lassnig, C.-A. Eberle, M. W. Górna, C. L. Baumann, T. R. Burkard, T. Bürckstümmer, A. Stefanovic, S. Krieger, K. L. Bennett, T. Rülicke, F. Weber, J. Colinge, M. Müller, G. Superti-Furga (2011): IFIT1 is an antiviral protein that recognises 5’-triphosphate RNA. Nature Immunology 12: 624-630

Reviews

1. HALLER, O., G. KOCHS, F. WEBER (2006): The Interferon Response Circuit: Induction and Suppression by Pathogenic Viruses. Virology 344:119-130

2. THIMME, R., V. LOHMANN, F. WEBER (2006): A target on the move: Innate and adaptive immune escape strategies of hepatitis C virus. Antiviral Research 69:129–141

3. WEBER, F., O. HALLER (2007): Viral suppression of the interferon system. Biochimie 89:836-842

4. HALLER, O., G. KOCHS, F. WEBER (2007): Interferon, Mx, and viral countermeasures. Cytokine Growth Factor Rev. 18:425-33.

5. THIEL, V., F. WEBER (2008): Interferon and cytokine responses to SARS-coronavirus infection. Cytokine Growth Factor Rev. 19: 121-132

6. WEBER, F., A. MIRAZIMI (2008): Interferon and Cytokine responses to Crimean Congo Hemorrhagic Fever Virus; an emerging and neglected viral zonoosis. Cytokine Growth Factor Rev. 19: 395-404

7. ELLIOTT, R.M., F. WEBER (2009): Bunyaviruses and the Type I Interferon System. Viruses 1, 1003-1021.

8. BOULOY, M., F. WEBER (2010): Molecular Biology of Rift Valley fever virus. Open Virology Journal 4, 8-17

9. KURI, T., F. WEBER (2010): Interferon interplay helps tissue cells to cope with SARS-Coronavirus infection. Virulence 1:273-275

10. ÖVERBY, A.K., F. Weber (2011): Hiding from intracellular pattern recognition receptors, a passive strategy of flavivirus immune evasion. Virulence 2: 238-240

Book chapters

1. SPIEGEL, M., F. WEBER (2007): SARS-Coronavirus and the antiviral cytokine response. In: Coronaviruses: Molecular Biology and Diseases (Editor: Volker Thiel) Caister Academic Press. p. 239-255

2. HALLER, O., F. WEBER (2007): Pathogenic viruses: smart manipulators of the interferon system. Curr. Top. Microbiol. Immunol. 316:315–334

3. WEBER, F. (2008): Innate immunity: Introduction. In: Encyclopedia of Virology, 3rd Edition. Elsevier Ltd, Oxford.  p. 111-117

4. WEBER, F., R. M. ELLIOTT (2009): Bunyaviruses and innate immunity. In: Cellular Signaling and Innate Immune Responses to RNA Virus infections (Editors: A. R. Brasier et al.) ASM Press, Washington, D.C. Chapter 18: p. 287-299

5. HALLER, O., F. WEBER (2009): The Interferon Response Circuit in Antiviral Host Defense. Verhandelingen van de Koninklijke Academie voor Geneeskunde van Belgie 71(1-2):73-86.