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Article ; Online: SARS-CoV-2 nucleocapsid protein inhibits the PKR-mediated integrated stress response through RNA-binding domain N2b.

Aloise, Chiara / Schipper, Jelle G / van Vliet, Arno / Oymans, Judith / Donselaar, Tim / Hurdiss, Daniel L / de Groot, Raoul J / van Kuppeveld, Frank J M

PLoS pathogens

2023 Volume 19, Issue 8, Page(s) e1011582

Abstract: The nucleocapsid protein N of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enwraps and condenses the viral genome for packaging but is also an antagonist of the innate antiviral defense. It suppresses the integrated stress response (ISR), ...

Abstract	The nucleocapsid protein N of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enwraps and condenses the viral genome for packaging but is also an antagonist of the innate antiviral defense. It suppresses the integrated stress response (ISR), purportedly by interacting with stress granule (SG) assembly factors G3BP1 and 2, and inhibits type I interferon responses. To elucidate its mode of action, we systematically deleted and over-expressed distinct regions and domains. We show that N via domain N2b blocks PKR-mediated ISR activation, as measured by suppression of ISR-induced translational arrest and SG formation. N2b mutations that prevent dsRNA binding abrogate these activities also when introduced in the intact N protein. Substitutions reported to block post-translation modifications of N or its interaction with G3BP1/2 did not have a detectable additive effect. In an encephalomyocarditis virus-based infection model, N2b - but not a derivative defective in RNA binding-prevented PKR activation, inhibited β-interferon expression and promoted virus replication. Apparently, SARS-CoV-2 N inhibits innate immunity by sequestering dsRNA to prevent activation of PKR and RIG-I-like receptors. Similar observations were made for the N protein of human coronavirus 229E, suggesting that this may be a general trait conserved among members of other orthocoronavirus (sub)genera.
MeSH term(s)	Humans ; SARS-CoV-2/genetics ; DNA Helicases ; COVID-19 ; Poly-ADP-Ribose Binding Proteins ; RNA Helicases ; RNA Recognition Motif Proteins/genetics ; RNA-Binding Motifs ; Encephalomyocarditis virus
Chemical Substances	DNA Helicases (EC 3.6.4.-) ; Poly-ADP-Ribose Binding Proteins ; RNA Helicases (EC 3.6.4.13) ; RNA Recognition Motif Proteins ; G3BP1 protein, human (EC 3.6.4.12)
Language	English
Publishing date	2023-08-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1011582
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Avidity engineering of human heavy-chain-only antibodies mitigates neutralization resistance of SARS-CoV-2 variants.

Du, Wenjuan / Janssens, Rick / Mykytyn, Anna Z / Li, Wentao / Drabek, Dubravka / van Haperen, Rien / Chatziandreou, Marianthi / Rissmann, Melanie / van der Lee, Joline / van Dortmondt, Melissa / Martin, Itziar Serna / van Kuppeveld, Frank J M / Hurdiss, Daniel L / Haagmans, Bart L / Grosveld, Frank / Bosch, Berend-Jan

Frontiers in immunology

2023 Volume 14, Page(s) 1111385

Abstract: Emerging SARS-CoV-2 variants have accrued mutations within the spike protein rendering most therapeutic monoclonal antibodies against COVID-19 ineffective. Hence there is an unmet need for broad-spectrum mAb treatments for COVID-19 that are more ... ...

Abstract	Emerging SARS-CoV-2 variants have accrued mutations within the spike protein rendering most therapeutic monoclonal antibodies against COVID-19 ineffective. Hence there is an unmet need for broad-spectrum mAb treatments for COVID-19 that are more resistant to antigenically drifted SARS-CoV-2 variants. Here we describe the design of a biparatopic heavy-chain-only antibody consisting of six antigen binding sites recognizing two distinct epitopes in the spike protein NTD and RBD. The hexavalent antibody showed potent neutralizing activity against SARS-CoV-2 and variants of concern, including the Omicron sub-lineages BA.1, BA.2, BA.4 and BA.5, whereas the parental components had lost Omicron neutralization potency. We demonstrate that the tethered design mitigates the substantial decrease in spike trimer affinity seen for escape mutations for the hexamer components. The hexavalent antibody protected against SARS-CoV-2 infection in a hamster model. This work provides a framework for designing therapeutic antibodies to overcome antibody neutralization escape of emerging SARS-CoV-2 variants.
MeSH term(s)	Animals ; Cricetinae ; Humans ; SARS-CoV-2/genetics ; COVID-19 ; Spike Glycoprotein, Coronavirus/genetics ; Immunoglobulin Heavy Chains/genetics ; Antibodies, Monoclonal
Chemical Substances	Spike Glycoprotein, Coronavirus ; Immunoglobulin Heavy Chains ; Antibodies, Monoclonal ; spike protein, SARS-CoV-2
Language	English
Publishing date	2023-02-21
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1111385
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Article ; Online: Sialoglycan binding triggers spike opening in a human coronavirus.

Pronker, Matti F / Creutznacher, Robert / Drulyte, Ieva / Hulswit, Ruben J G / Li, Zeshi / van Kuppeveld, Frank J M / Snijder, Joost / Lang, Yifei / Bosch, Berend-Jan / Boons, Geert-Jan / Frank, Martin / de Groot, Raoul J / Hurdiss, Daniel L

Nature

2023 Volume 624, Issue 7990, Page(s) 201–206

Abstract: Coronavirus spike proteins mediate receptor binding and membrane fusion, making them prime targets for neutralizing antibodies. In the cases of severe acute respiratory syndrome coronavirus, severe acute respiratory syndrome coronavirus 2 and Middle East ...

Abstract	Coronavirus spike proteins mediate receptor binding and membrane fusion, making them prime targets for neutralizing antibodies. In the cases of severe acute respiratory syndrome coronavirus, severe acute respiratory syndrome coronavirus 2 and Middle East respiratory syndrome coronavirus, spike proteins transition freely between open and closed conformations to balance host cell attachment and immune evasion
MeSH term(s)	Humans ; Allosteric Regulation ; Betacoronavirus/chemistry ; Betacoronavirus/ultrastructure ; Common Cold/virology ; Cryoelectron Microscopy ; Molecular Dynamics Simulation ; Polysaccharides/chemistry ; Polysaccharides/metabolism ; Protein Binding ; Protein Conformation ; Sialic Acids/chemistry ; Sialic Acids/metabolism ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/metabolism ; Spike Glycoprotein, Coronavirus/ultrastructure ; Immune Evasion
Chemical Substances	Polysaccharides ; Sialic Acids ; Spike Glycoprotein, Coronavirus
Language	English
Publishing date	2023-10-04
Publishing country	England
Document type	Journal Article
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/s41586-023-06599-z
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Zs.A 26: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 9: Show issues
Zs.MO 244: Show issues

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Article ; Online: SARS-CoV-2 nucleocapsid protein inhibits the stress response through RNA-binding domain N2b

Aloise, Chiara / Schipper, Jelle G. / Donselaar, Tim / Hurdiss, Daniel L. / de Groot, Raoul J. / van Kuppeveld, Frank J.M.

bioRxiv

Abstract	The nucleocapsid protein N of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enwraps and condenses the viral genome for packaging but is also an antagonist of the innate antiviral defense. It suppresses the integrated stress response (ISR), purportedly by interacting with stress granule (SG) assembly factors G3BP1 and 2, and inhibits type I interferon responses. To elucidate its mode of action, we systematically deleted and over-expressed distinct regions and domains. We show that N via domain N2b blocks PKR-mediated ISR activation, as measured by suppression of ISR-induced translational arrest and SG formation. N2b mutations that prevent dsRNA binding abrogate these activities also when introduced in the intact N protein. Substitutions reported to block post-translation modifications of N or its interaction with G3BP1/2 did not have a detectable additive effect. In an encephalomyocarditis virus-based infection model, N2b - but not a derivative defective in RNA binding - prevented PKR activation, inhibited β-interferon expression and promoted virus replication. Apparently, SARS-CoV-2 N inhibits innate immunity by sequestering dsRNA to prevent activation of PKR and RIG-I-like receptors. Observations made for the N protein of human coronavirus 229E suggests that this may be a general trait conserved among members of other orthocoronavirus (sub)genera.
Keywords	covid19
Language	English
Publishing date	2022-09-02
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2022.09.02.506332
Database	COVID19

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Article ; Online: Dynamics in the murine norovirus capsid revealed by high-resolution cryo-EM.

Snowden, Joseph S / Hurdiss, Daniel L / Adeyemi, Oluwapelumi O / Ranson, Neil A / Herod, Morgan R / Stonehouse, Nicola J

PLoS biology

2020 Volume 18, Issue 3, Page(s) e3000649

Abstract: Icosahedral viral capsids must undergo conformational rearrangements to coordinate essential processes during the viral life cycle. Capturing such conformational flexibility has been technically challenging yet could be key for developing rational ... ...

Abstract	Icosahedral viral capsids must undergo conformational rearrangements to coordinate essential processes during the viral life cycle. Capturing such conformational flexibility has been technically challenging yet could be key for developing rational therapeutic agents to combat infections. Noroviruses are nonenveloped, icosahedral viruses of global importance to human health. They are a common cause of acute gastroenteritis, yet no vaccines or specific antiviral agents are available. Here, we use genetics and cryo-electron microscopy (cryo-EM) to study the high-resolution solution structures of murine norovirus as a model for human viruses. By comparing our 3 structures (at 2.9- to 3.1-Å resolution), we show that whilst there is little change to the shell domain of the capsid, the radiating protruding domains are flexible, adopting distinct states both independently and synchronously. In doing so, the capsids sample a range of conformational space, with implications for maintaining virion stability and infectivity.
MeSH term(s)	Animals ; Capsid/chemistry ; Capsid Proteins/chemistry ; Capsid Proteins/genetics ; Cryoelectron Microscopy ; Dimerization ; Hot Temperature ; Mice ; Models, Molecular ; Mutation ; Norovirus/chemistry ; Norovirus/genetics ; Norovirus/pathogenicity ; Protein Domains ; RAW 264.7 Cells ; Structure-Activity Relationship
Chemical Substances	Capsid Proteins
Language	English
Publishing date	2020-03-31
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2126776-5
ISSN	1545-7885 ; 1544-9173
ISSN (online)	1545-7885
ISSN	1544-9173
DOI	10.1371/journal.pbio.3000649
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Zs.A 6193: Show issues

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bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Fluoxetine targets an allosteric site in the enterovirus 2C AAA+ ATPase and stabilizes a ring-shaped hexameric complex.

Hurdiss, Daniel L / El Kazzi, Priscila / Bauer, Lisa / Papageorgiou, Nicolas / Ferron, François P / Donselaar, Tim / van Vliet, Arno L W / Shamorkina, Tatiana M / Snijder, Joost / Canard, Bruno / Decroly, Etienne / Brancale, Andrea / Zeev-Ben-Mordehai, Tzviya / Förster, Friedrich / van Kuppeveld, Frank J M / Coutard, Bruno

Science advances

2022 Volume 8, Issue 1, Page(s) eabj7615

Abstract: Enteroviruses are globally prevalent human pathogens responsible for many diseases. The nonstructural protein 2C is a AAA+ helicase and plays a key role in enterovirus replication. Drug repurposing screens identified 2C-targeting compounds such as ... ...

Abstract	Enteroviruses are globally prevalent human pathogens responsible for many diseases. The nonstructural protein 2C is a AAA+ helicase and plays a key role in enterovirus replication. Drug repurposing screens identified 2C-targeting compounds such as fluoxetine and dibucaine, but how they inhibit 2C is unknown. Here, we present a crystal structure of the soluble and monomeric fragment of coxsackievirus B3 2C protein in complex with (
Language	English
Publishing date	2022-01-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.abj7615
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Article ; Online: The Structure of an Infectious Human Polyomavirus and Its Interactions with Cellular Receptors.

Hurdiss, Daniel L / Frank, Martin / Snowden, Joseph S / Macdonald, Andrew / Ranson, Neil A

Structure (London, England : 1993)

2018 Volume 26, Issue 6, Page(s) 839–847.e3

Abstract: BK polyomavirus (BKV) causes polyomavirus-associated nephropathy and hemorrhagic cystitis in immunosuppressed patients. These are diseases for which we currently have limited treatment options, but potential therapies could include pre-transplant ... ...

Abstract	BK polyomavirus (BKV) causes polyomavirus-associated nephropathy and hemorrhagic cystitis in immunosuppressed patients. These are diseases for which we currently have limited treatment options, but potential therapies could include pre-transplant vaccination with a multivalent BKV vaccine or therapeutics which inhibit capsid assembly or block attachment and entry into target cells. A useful tool in such efforts would be a high-resolution structure of the infectious BKV virion and how this interacts with its full repertoire of cellular receptors. We present the 3.4-Å cryoelectron microscopy structure of native, infectious BKV in complex with the receptor fragment of GT1b ganglioside. We also present structural evidence that BKV can utilize glycosaminoglycans as attachment receptors. This work highlights features that underpin capsid stability and provides a platform for rational design and development of urgently needed pharmacological interventions for BKV-associated diseases.
MeSH term(s)	BK Virus/chemistry ; BK Virus/metabolism ; Binding Sites ; Capsid Proteins/chemistry ; Capsid Proteins/metabolism ; Cryoelectron Microscopy ; Crystallography, X-Ray ; Gangliosides/metabolism ; Humans ; Models, Molecular ; Polyomavirus Infections/metabolism ; Polyomavirus Infections/virology ; Protein Multimerization ; Virion/chemistry ; Virion/metabolism
Chemical Substances	Capsid Proteins ; Gangliosides ; trisialoganglioside GT1 (59247-13-1)
Language	English
Publishing date	2018-04-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1213087-4
ISSN	1878-4186 ; 0969-2126
ISSN (online)	1878-4186
ISSN	0969-2126
DOI	10.1016/j.str.2018.03.019
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Zs.A 4141: Show issues

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Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Antigenic structure of the human coronavirus OC43 spike reveals exposed and occluded neutralizing epitopes.

Wang, Chunyan / Hesketh, Emma L / Shamorkina, Tatiana M / Li, Wentao / Franken, Peter J / Drabek, Dubravka / van Haperen, Rien / Townend, Sarah / van Kuppeveld, Frank J M / Grosveld, Frank / Ranson, Neil A / Snijder, Joost / de Groot, Raoul J / Hurdiss, Daniel L / Bosch, Berend-Jan

Nature communications

2022 Volume 13, Issue 1, Page(s) 2921

Abstract: Human coronavirus OC43 is a globally circulating common cold virus sustained by recurrent reinfections. How it persists in the population and defies existing herd immunity is unknown. Here we focus on viral glycoprotein S, the target for neutralizing ... ...

Abstract	Human coronavirus OC43 is a globally circulating common cold virus sustained by recurrent reinfections. How it persists in the population and defies existing herd immunity is unknown. Here we focus on viral glycoprotein S, the target for neutralizing antibodies, and provide an in-depth analysis of its antigenic structure. Neutralizing antibodies are directed to the sialoglycan-receptor binding site in S1
MeSH term(s)	Antibodies, Monoclonal ; Antibodies, Neutralizing ; Antibodies, Viral ; COVID-19 ; Coronavirus OC43, Human/metabolism ; Epitopes ; Humans ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus
Chemical Substances	Antibodies, Monoclonal ; Antibodies, Neutralizing ; Antibodies, Viral ; Epitopes ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2022-05-25
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-30658-0
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Sialoglycan binding triggers spike opening in a human coronavirus

Pronker, Matti F. / Creutznacher, Robert / Drulyte, Ieva / Hulswit, Ruben J.G. / Li, Zeshi / van Kuppeveld, Frank J.M. / Snijder, Joost / Lang, Yifei / Bosch, Berend-Jan / Boons, Geert-Jan / Frank, Martin / Groot, Raoul J. de / Hurdiss, Daniel L.

bioRxiv

Abstract: Coronavirus (CoV) spikes mediate receptor binding and membrane fusion, making them prime targets for neutralising antibodies. In the cases of SARS-CoV, SARS-CoV-2, and MERS-CoV, spikes transition freely between open and closed conformations to balance ... ...

Abstract	Coronavirus (CoV) spikes mediate receptor binding and membrane fusion, making them prime targets for neutralising antibodies. In the cases of SARS-CoV, SARS-CoV-2, and MERS-CoV, spikes transition freely between open and closed conformations to balance host cell attachment and immune evasion. The open conformation exposes domain S1<sup>B</sup>, allowing it to bind to proteinaceous cell surface receptors. It also facilitates protein refolding during spike-mediated membrane fusion. However, with a single exception, the pre-fusion spikes of all other CoVs studied so far have been observed exclusively in the closed state. This raises the possibility of regulation, where spikes more commonly transition to open states in response to specific cues, rather than spontaneously. In our study, using cryo-EM and molecular dynamics simulations, we show that the spike protein of the common cold human coronavirus HKU1 undergoes local and long-range conformational changes upon binding a sialoglycan-based primary receptor to domain S1<sup>A</sup>. This binding triggers the transition of S1<sup>B</sup> domains to the open state via allosteric inter-domain cross-talk. Our findings paint a more elaborate picture of CoV attachment, with possibilities of dual receptor usage and priming of entry as a means of immune escape.
Keywords	covid19
Language	English
Publishing date	2023-04-20
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2023.04.20.536837
Database	COVID19

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Article: Plant-Made Nervous Necrosis Virus-Like Particles Protect Fish Against Disease.

Marsian, Johanna / Hurdiss, Daniel L / Ranson, Neil A / Ritala, Anneli / Paley, Richard / Cano, Irene / Lomonossoff, George P

Frontiers in plant science

2019 Volume 10, Page(s) 880

Abstract: Virus-like particles (VLPs) of the fish virus, Atlantic Cod Nervous necrosis virus (ACNNV), were successfully produced by transient expression of the coat protein ... ...

Abstract	Virus-like particles (VLPs) of the fish virus, Atlantic Cod Nervous necrosis virus (ACNNV), were successfully produced by transient expression of the coat protein in
Language	English
Publishing date	2019-07-09
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2711035-7
ISSN	1664-462X
ISSN	1664-462X
DOI	10.3389/fpls.2019.00880
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