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Professor F.J.M. (Frank) van Kuppeveld, PhD

Tuesday 23 October 2012

Virus-host interactions, antivirals and vaccine development
The RNA viruses are the largest class of viruses and include many pathogens of humans and animals. As such, they are major cause of morbidity and mortality in humans and animals and are responsible for huge economic losses worldwide. Research at the Virology division aims to unravel the structure, entry, replication, and molecular pathogenesis of several RNA viruses that are of human clinical and veterinary relevance. These include the nidoviruses (i.e. corona-, toro- and arteriviruses), picornaviruses (e.g. entero-, cardio, and aphthoviruses), influenza A virus, bunyaviruses (e.g. Rift Valley fever virus and Crimean-Congo hemorrhagic fever virus), and respiratory syncytial virus. Our ultimate goal is to translate this knowledge into the development of novel therapeutic and prophylactic strategies.

Virus structure and entry
We are interested in virus structure, virus-cell attachment, subsequent endocytic uptake of virus particles and fusion between viral and host membranes. To this end, we developed novels systems for the expression of recombinant viral attachment/ fusion proteins, which are applied to study the interaction of viruses with their receptors. Our approach is inherently multidisciplinary entailing molecular virology (reverse and forward genetics), structural biology (crystallography, electron microscopy), glycobiology (e.g. glycan array analysis), biophysics, biochemistry, bio-informatics, and in vivo studies.

Virus replication
Making use of state-of-the-art virological, biochemical, cell biological (e.g. siRNA screens), and microscopy (e.g. life cell imaging and tomography) approaches, we study the role of the viral non-structural proteins and (hijacked) host factors in the formation and the architecture of the membrane-associated replication organelles as well as in the process of viral RNA synthesis that takes place in these specialized replication sites.

Vaccines and antiviral drugs
In addition, the Virology Division develops innovative vaccines, using recombinant protein and virus-like particle technology as well as live attenuated virus approaches. As there are very few effective antiviral drugs to treat virus infections, we also aim to identify potent and safe inhibitors of virus replication and to elucidate their mode of action.

Key publications
1. Feng Q, Hato S, Langereis M, Zoll J, Virgen-Slane R, Peisley A, Hur S, Semler B, van Rij R, van Kuppeveld F. MDA5 detects the double-stranded RNA replicative form in picornavirus-infected cells. Cell Reports. 2012 in press.
2. de Boer SM, Kortekaas J, Spel L, Rottier PJ, Moormann RJ and Bosch BJ. Acid-activated structural reorganization of the Rift Valley fever virus Gc fusion protein. J Virol. 2012 Oct 3. [Epub ahead of print]
3. de Boer SM, Kortekaas J, de Haan CA, Rottier PJ, Moormann RJ and Bosch BJ. Heparan sulfate facilitates Rift Valley fever virus entry into the cell. J Virol. 2012 Sep 26. [Epub ahead of print]
4. van der Schaar HM, van der Linden L, Lanke KH, Strating JR, Pürstinger G, de Vries E, de Haan CA, Neyts J, van Kuppeveld FJ. Coxsackievirus mutants that can bypass host factor PI4KIIIβ and the need for high levels of PI4P lipids for replication. Cell Res. 2012 Sep 4. doi: 10.1038/cr.2012.129.
5. de Vries RP, Smit CH, de Bruin E, Rigter A, de Vries E, Cornelissen LA, Eggink D, Chung NP, Moore JP, Sanders RW, Hokke CH, Koopmans M, Rottier PJ, de Haan CA. Glycan-dependent immunogenicity of recombinant soluble trimeric hemagglutinin. J Virol. 2012 Nov;86(21):11735-44.
6. Risco, C., Sanmartín-Conesa, E., Tzeng, W.P., Frey, T.K., Seybold, V., de Groot, R.J. (2012) Specific, sensitive, high-resolution detection of protein molecules in eukaryotic cells using metal-tagging transmission electron microscopy. Structure 20, 759-66.
7. Langereis, M.A., Zeng, Q., Heesters, B., Huizinga, E.G. and de Groot, R.J. (2012) Structure of the Murine Coronavirus HE Receptor Binding Site: a Major Shift in Ligand Specificity by Modest Changes in Binding-Site Architecture. PLOS Pathogens 8, e1002492.
8. de Vries E, de Vries RP, Wienholts MJ, Floris CE, Jacobs MS, van den Heuvel A, Rottier PJ, de Haan CA. Influenza A virus entry into cells lacking sialylated N-glycans. Proc Natl Acad Sci U S A. 2012 May 8;109(19):7457-62.
9. de Vries E, Tscherne DM, Wienholts MJ, Cobos-Jiménez V, Scholte F,García-Sastre A, Rottier PJ, de Haan CA. Dissection of the influenza A virus endocytic routes reveals macropinocytosis as an alternative entry pathway. PLoS Pathog. 2011 Mar;7(3):e1001329.
10. de Vries RP, de Vries E, Moore KS, Rigter A, Rottier PJ, de Haan CA. Only two residues are responsible for the dramatic difference in receptor binding between swine and new pandemic H1 hemagglutinin. J Biol Chem. 2011 Feb 18;286(7):5868-75.
11. Hagemeijer MC, Ulasli M, Vonk AM, Reggiori F, Rottier PJ, de Haan CA. Mobility and interactions of coronavirus nonstructural protein 4. J Virol. 2011 May;85(9):4572-7.
12. Limpens RW, van der Schaar HM, Kumar D, Koster AJ, Snijder EJ, van Kuppeveld FJ, Bárcena M. The transformation of enterovirus replication structures: a three-dimensional study of single- and double-membrane compartments. MBio. 2011 Oct 4;2(5).
13. Hsu NY, Ilnytska O, Belov G, Santiana M, Chen YH, Takvorian PM, Pau C, van der Schaar H, Kaushik-Basu N, Balla T, Cameron CE, Ehrenfeld E, van Kuppeveld FJ, Altan-Bonnet N. Viral reorganization of the secretory pathway generates distinct organelles for RNA replication. Cell. 2010 May 28;141(5):799-811
14. de Boer SM, Kortekaas J, Antonis AF, Kant J, van Oploo JL, Rottier PJ, Moormann RJ and Bosch BJ. Rift Valley fever virus subunit vaccines confer complete protection against a lethal virus challenge. Vaccine. 2010 Mar 8;28(11):2330-9.
15. Barcena, M., G. T. Oostergetel, W. Bartelink, F. G. Faas, A. Verkleij, P. J. Rottier, A. J. Koster and B.J. Bosch. 2009. Cryo-electron tomography of mouse hepatitis virus: Insights into the structure of the coronavirion. Proc Natl Acad Sci U S A. Jan. 5.
16. Raaben M, Prins HJ, Martens AC, Rottier PJ, De Haan CA. Non-invasive imaging of mouse hepatitis coronavirus infection reveals determinants of viral replication and spread in vivo. Cell Microbiol. 2009 May;11(5):825-41.
17. Langereis, M.A,, Zeng, Q., Gerwig, G.J., Frey, B., von Itzstein, M., Kamerling, J.P., de Groot, R.J.* and Huizinga E.G.* (2009) Structural basis for ligand and substrate recognition by torovirus hemagglutinin esterases. Proc. Natl. Acad. Sci. USA 106, 15897-15902. *Shared senior authorship
18. Zeng, Q., Langereis, M.A., van Vliet, A.L.W., Huizinga, E.G. and de Groot, R.J. (2008) Structure of coronavirus hemagglutinin-esterase offers insight into corona- and influenza virus evolution. Proc. Natl. Acad. Sci. USA 105, 9065-9069.
19. Verheije MH, Raaben M, Mari M, Te Lintelo EG, Reggiori F, van Kuppeveld FJ, Rottier PJ, de Haan CA. Mouse hepatitis coronavirus RNA replication depends on GBF1-mediated ARF1 activation. PLoS Pathog. 2008 Jun 13;4(6):e1000088.

E-mail: F.J.M.vanKuppeveld@uu.nl
Website: Utrecht University

Principle InvestigatorsPost doc
Berend Jan BoschHilde van Tongeren
Herman Egberink
Raoul de Groot
Xander de Haan
Erik de Vries

PhD projects
Lucian AlbulescuRole of cellular factors involved in picornavirus replication
Jim BaggenViral hijacking of host cell factors and membranes for replication organelle formation
Mark BakkersSweet Attachment: structural and Biological consequences of viral adaptation to specific sialic acid receptor determinants
Christina DorobantuHijacking cellular membranes for picornavirus genomic replication
Huib RabouwThe role of coronavirus accessory proteins in innate immune evasion
PhD thesis 2014
Qian FengInduction and Suppression of the Innate Antiviral Responses by Picornaviruses