Research & Awards

The central themes in my research are the interaction between viruses and their host, and the development of antiviral strategies. My work mainly focuses on picornaviruses (a large family of (+)RNA viruses that includes many clinically and economically important pathogens for humans - e.g. poliovirus, EV-A71, EV-D68, coxsackievirus and rhinovirus - and animals, such as FMDV and EMCV) and coronaviruses (e.g. SARS-CoV-2 and MERS-CoV).

Research has been awarded by personal ERC Advanced Grant (2022), VICI (2011) and VIDI (2003) grants from NWO (the Netherlands Organization for Scientific Research). Research was further awarded by the Beijerinck Premium (award from the Royal Netherlands Academy of Arts and Sciences, KNAW) (2004) and the N4i (Nijmegen Institute for Infection, Inflammation & Immunity) Senior Scientist award (2011).

Furthermore, I have coordinated ANTIVIRALS, a H2020 Marie Curie European Training Network (ETN) on "antiviral drug development” (2015-2019, www.antivirals-etn.eu), and EUVIRNA, an FP7 Marie Curie Initial Training Network (ITN) on “+RNA virus replication and antiviral drug development” (2011-2015, www.euvirna.eu).

Brief summary of research

My current research focuses on 1) virus receptors and entry mechanisms, 2) viral genome replication, 3) development of antiviral drugs, and 4) innate host responses and viral countermeasures.

For these studies, we make use of state-of-the-art virological, biochemical, cell biological (e.g. CRISPR-Cas9 KO, haploid cells, siRNA screens), microscopy (e.g. life cell imaging and tomography), drug screen and structure-based drug design approaches.

1) Virus structure, receptors and entry mechanisms: We aim to identify the receptors and entry pathways used by picornaviruses to infect cells. Recently, we identified sialic acid as an important factor for binding and entry of enterovirus-D68, an important and emerging respiratory enterovirus. 

• Baggen J, Thibaut H, Staring J, Jae L, Liu Y, Guo H, Slager J, de Bruin J, van Vliet A, Blomen V, Overduin P, Sheng J, de Haan C, de Vries E, Meijer A, Rossmann M, Brummelkamp T, van Kuppeveld F. 2016. Enterovirus D68 receptor requirements unveiled by haploid genetics. Proc Natl Acad Sci USA 113:1399-404.

• Liu Y, Sheng J, Baggen J, Meng G, Xiao C, Thibaut H, van Kuppeveld F, Rossmann M. 2015. Sialic acid-dependent cell entry of human enterovirus D68. Nat Commun 6:8865.

2) Virus replication: All (+)RNA viruses rearrange intracellular host membranes to create so-called replication organelles. We study the role of the viral non-structural proteins and (hijacked) host factors in the formation and the architecture of  enteroviral replication organelles as well as in the process of viral RNA replication that takes place in these specialized replication sites.  

• van der Schaar H, Dorobantu C, Albulescu L, Strating J, van Kuppeveld F. 2016. Fat(al) attraction: Picornaviruses usurp lipid transfer at membrane contact sites to create replication organelles. Trends Microbiol 24:535-46.

• Dorobantu C, Albulescu L, Harak C, Feng-Jurgeit Q, van Kampen M, Strating J, Gorbalenya A, Volhmann V, van der Schaar H,  van Kuppeveld F. 2015 Modulation of the host lipid landscape to promote RNA virus replication: the picornavirus encephalomyocarditis virus converges on the pathway used by hepatitis C virus. PLoS Pathog 11:e1005185.

• Strating J, van der Linden L, Albulescu L, Bigay J, Arita M, Delang L, Leyssen P, van der Schaar H, Lanke K, Thibaut H, Ulferts R, Drin G, Schlinck N, Wubbolts R, Sever N, Head S, Liu J, Beachy P, De Matteis M, Shair M, Olkkonen V, Neyts J, van Kuppeveld F. 2015. Itraconazole inhibits enterovirus replication by targeting the oxysterol binding protein. Cell Rep 10:600-615.

• van der Schaar H, van der Linden L, Lanke K, Strating J, Purstinger G, de Vries E, de Haan C, Neyts J, van Kuppeveld F. 2012. Coxsackievirus mutants that can bypass host factor PI4KIIIβ and the need for high levels of PI4P lipids for replication. Cell Res 22:1576-1592.

• Hsu N, Ilnytska O, Belov G, Santiana M, Chen Y, Takvorian P, Pau C, van der Schaar H, Kaushik-Basu N, Balla T, Cameron C, Ehrenfeld E, van Kuppeveld F, Altan-Bonnet N. 2010. Viral reorganization of the secretory pathway generates distinct organelles for RNA replication. Cell 141:799-811.

3) Antiviral strategies: Thus far, there are no effective antiviral drugs to treat picornavirus infections. The goal of this research line is to identify potent and safe broad-range  inhibitors of picornavirus replication and to elucidate their mode of action. We identified several inhibitors of viral proteins (e.g. 2C^ATPase, 3D^pol) as well as of essential host factors (e.g. PI4KIIIβ, OSBP). 

• Ulferts R, de Boer M, van der Linden L, Bauer L, Lyoo H, Maté M, Lichière J, Canard B, Lelieveld D, Omta W, Egan D, Coutard B, van Kuppeveld F. 2016. Screening of a library of FDA-approved drugs identifies several enterovirus replicaton inhibitors that target viral protein 2C. Antimicrob Agents Chemother pii: AAC.02182-15.

• Van der Linden L, Vives-Adrian L, Selisko B, Ferrer-Orta, Liu X, Lanke K, Ulferts R, de Palma A, Tanchis F, Goris N, Lefebvre D, de Clercq K, Leyssen P, Lacroix C, Purstinger G, Coutard B, Canard B, Boehr D, Arnold J, Cameron C, Verdaguer N, Neyts J, van Kuppeveld F. 2015. The RNA template channel of the RNA-dependent RNA polymerase as a target for development of antiviral therapy of multiple genera with a virus family. PLoS Pathog e1004733.

• Strating J, van der Linden L, Albulescu L, Bigay J, Arita M, Delang L, Leyssen P, van der Schaar H, Lanke K, Thibaut H, Ulferts R, Drin G, Schlinck N, Wubbolts R, Sever N, Head S, Liu J, Beachy P, De Matteis M, Shair M, Olkkonen V, Neyts J, van Kuppeveld F. 2015. Itraconazole inhibits enterovirus replication by targeting the oxysterol binding protein. Cell Rep 10:600-615.

• Ulferts R, van der Linden L, Thibaut H, Lanke K, Leyssen P, Coutard B, de Palma A, Canard B, Neyts J, van Kuppeveld F. 2013. Selective serotonin reuptake inhibitor fluoxetine inhibits replication of human enterovirus B and D by targeting viral protein 2C. Antimicrob Agents Chemother 57:1952-1956.

• van der Schaar H, Leyssen P, Thibaut H, de Palma A, van der Linden L, Lanke K, Lacroix C, Verbeken E, Conrath K, Macleod A, Mitchell D, Palmer N, van de Poel H, Andrews M, Neyts J, van Kuppeveld F. 2013. A novel, broad-spectrum inhibitor of enterovirus replication that targets host cell factor phosphatidylinositol 4-kinase IIIβ. Antimicrob Agents Chemother 57:4971-4981.

   

4) Innate responses. We study (i) how intracellular RNA sensors (e.g. RIG-I and MDA5) discriminate viral RNA from host cell RNA and how they signal to trigger innate type I IFN responses, and (ii) the role of the integrated stress response as an antiviral pathway. Furthermore, we study how picornaviruses and coronaviruses actively manipulate the IFN and stress response pathways to suppress these infection-limiting host responses.

• Rabouw H, Langereis M, Knaap R, Dalebout T, Canton J, Sola I, Enjuanes L, Bredenbeek P, Kikkert M, de Groot R, van Kuppeveld F. 2016. Middle East Respiratory Coronavirus Accessory Protein 4a Inhibits PKR-Mediated Antiviral Stress Responses. PLoS Pathog 12:e1005982.

• Langereis M, Rabouw H, Holwerda M, Visser L, van Kuppeveld F. 2015. cGAS and STING knockout rescues virus infection of plasmid DNA-transfected cells. J Virol 89:11169-11173.

• Feng Q, Langereis M, Lork M, Nguyen M, Hato S, Lanke K, Emdad L, Bhoopathi P, Fisher P, Lloyd R, van Kuppeveld F. 2014. Enteroviruses 2A^pro targets MDA5 and MAVS in infected cells. J Virol 88:3369-3378.

• Deddouche S, Goubau D, Rehwinkel J, Chakravarty P, Begum S, Maillard P, Borg A, Matthews N, Feng Q, van Kuppeveld F, Reis e Sousa C. 2014. Identification of an LGP2-associated MDA5 agonist in picornavirus-infected cells. eLife 3:e01535.

• Feng Q, Hato S, Langereis M, Zoll J, Virgen-Slane R, Peisley A, Hur S, Semler B, van Rij R, van Kuppeveld F. 2012. MDA5 detects the double-stranded RNA replicative form in picornavirus-infected cells. Cell Reports 2:1187-1196.