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Article ; Online: TLR4-Mediated Pathway Triggers Interferon-Independent G0 Arrest and Antiviral SAMHD1 Activity in Macrophages.

Mlcochova, Petra / Winstone, Helena / Zuliani-Alvarez, Lorena / Gupta, Ravindra K

2020 Volume 30, Issue 12, Page(s) 3972–3980.e5

Abstract: Macrophages exist predominantly in two distinct states, G0 and a G1-like state that is accompanied by phosphorylation of SAMHD1 at T592. Here, we demonstrate that Toll-like receptor 4 (TLR4) activation can potently induce G0 arrest and SAMHD1 ... ...

Abstract	Macrophages exist predominantly in two distinct states, G0 and a G1-like state that is accompanied by phosphorylation of SAMHD1 at T592. Here, we demonstrate that Toll-like receptor 4 (TLR4) activation can potently induce G0 arrest and SAMHD1 antiretroviral activity by an interferon (IFN)-independent pathway. This pathway requires TLR4 engagement with TRIF, but not involvement of TBK1 or IRF3. Exclusive Myd88 activators are unable to trigger G0 arrest or SAMHD1 dephosphorylation, demonstrating this arrest is also Myd88/nuclear factor κB (NF-κB) independent. The G0 arrest is accompanied by p21 upregulation and CDK1 depletion, consistent with the observed SAMHD1 dephosphorylation at T592. Furthermore, we show by SAMHD1 knockdown that the TLR4-activated pathway potently blocks HIV-1 infection in macrophages specifically via SAMHD1. Together, these data demonstrate that macrophages can mobilize an intrinsic cell arrest and anti-viral state by activating TLR4 prior to IFN secretion, thereby highlighting the importance of cell-cycle regulation as a response to pathogen-associated danger signals in macrophages.
MeSH term(s)	Antiviral Agents/metabolism ; Cell Cycle Checkpoints/drug effects ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Escherichia coli/metabolism ; Female ; HIV Infections/pathology ; Humans ; Interferons/metabolism ; Lipopolysaccharides/pharmacology ; Macrophages/metabolism ; Macrophages/virology ; Male ; Myeloid Differentiation Factor 88/metabolism ; Resting Phase, Cell Cycle/drug effects ; SAM Domain and HD Domain-Containing Protein 1/metabolism ; Signal Transduction/drug effects ; Toll-Like Receptor 4/metabolism ; Toll-Like Receptor 5/metabolism ; Up-Regulation/drug effects
Chemical Substances	Antiviral Agents ; Cyclin-Dependent Kinase Inhibitor p21 ; Lipopolysaccharides ; Myeloid Differentiation Factor 88 ; Toll-Like Receptor 4 ; Toll-Like Receptor 5 ; Interferons (9008-11-1) ; SAM Domain and HD Domain-Containing Protein 1 (EC 3.1.5.-)
Language	English
Publishing date	2020-03-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2020.03.008
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: A Nuclear Export Signal in KHNYN Required for Its Antiviral Activity Evolved as ZAP Emerged in Tetrapods.

Lista, Maria J / Ficarelli, Mattia / Wilson, Harry / Kmiec, Dorota / Youle, Rebecca L / Wanford, Joseph / Winstone, Helena / Odendall, Charlotte / Taylor, Ian A / Neil, Stuart J D / Swanson, Chad M

Journal of virology

2023 Volume 97, Issue 1, Page(s) e0087222

Abstract: The zinc finger antiviral protein (ZAP) inhibits viral replication by directly binding CpG dinucleotides in cytoplasmic viral RNA to inhibit protein synthesis and target the RNA for degradation. ZAP evolved in tetrapods and there are clear orthologs in ... ...

Abstract	The zinc finger antiviral protein (ZAP) inhibits viral replication by directly binding CpG dinucleotides in cytoplasmic viral RNA to inhibit protein synthesis and target the RNA for degradation. ZAP evolved in tetrapods and there are clear orthologs in reptiles, birds, and mammals. When ZAP emerged, other proteins may have evolved to become cofactors for its antiviral activity. KHNYN is a putative endoribonuclease that is required for ZAP to restrict retroviruses. To determine its evolutionary path after ZAP emerged, we compared KHNYN orthologs in mammals and reptiles to those in fish, which do not encode ZAP. This identified residues in KHNYN that are highly conserved in species that encode ZAP, including several in the CUBAN domain. The CUBAN domain interacts with NEDD8 and Cullin-RING E3 ubiquitin ligases. Deletion of the CUBAN domain decreased KHNYN antiviral activity, increased protein expression and increased nuclear localization. However, mutation of residues required for the CUBAN domain-NEDD8 interaction increased KHNYN abundance but did not affect its antiviral activity or cytoplasmic localization, indicating that Cullin-mediated degradation may control its homeostasis and regulation of protein turnover is separable from its antiviral activity. By contrast, the C-terminal residues in the CUBAN domain form a CRM1-dependent nuclear export signal (NES) that is required for its antiviral activity. Deletion or mutation of the NES increased KHNYN nuclear localization and decreased its interaction with ZAP. The final 2 positions of this NES are not present in fish KHNYN orthologs and we hypothesize their evolution allowed KHNYN to act as a ZAP cofactor.
MeSH term(s)	Animals ; Cullin Proteins/metabolism ; Interferons/genetics ; Nuclear Export Signals ; RNA, Viral/genetics ; Virus Replication/physiology ; RNA-Binding Proteins/genetics ; Ubiquitin-Protein Ligases/genetics ; Evolution, Molecular
Chemical Substances	Cullin Proteins ; Interferons (9008-11-1) ; Nuclear Export Signals ; RNA, Viral ; RNA-Binding Proteins ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
Language	English
Publishing date	2023-01-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/jvi.00872-22
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Article ; Online: The P681H Mutation in the Spike Glycoprotein of the Alpha Variant of SARS-CoV-2 Escapes IFITM Restriction and Is Necessary for Type I Interferon Resistance.

Lista, Maria Jose / Winstone, Helena / Wilson, Harry D / Dyer, Adam / Pickering, Suzanne / Galao, Rui Pedro / De Lorenzo, Giuditta / Cowton, Vanessa M / Furnon, Wilhelm / Suarez, Nicolas / Orton, Richard / Palmarini, Massimo / Patel, Arvind H / Snell, Luke / Nebbia, Gaia / Swanson, Chad / Neil, Stuart J D

Journal of virology

2022 Volume 96, Issue 23, Page(s) e0125022

Abstract: The appearance of new dominant variants of concern (VOC) of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) threatens the global response to the coronavirus disease 2019 (COVID-19) pandemic. Of these, the alpha variant (also known as B ... ...

Abstract	The appearance of new dominant variants of concern (VOC) of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) threatens the global response to the coronavirus disease 2019 (COVID-19) pandemic. Of these, the alpha variant (also known as B.1.1.7), which appeared initially in the United Kingdom, became the dominant variant in much of Europe and North America in the first half of 2021. The spike (S) glycoprotein of alpha acquired seven mutations and two deletions compared to the ancestral virus, including the P681H mutation adjacent to the polybasic cleavage site, which has been suggested to enhance S cleavage. Here, we show that the alpha spike protein confers a level of resistance to beta interferon (IFN-β) in human lung epithelial cells. This correlates with resistance to an entry restriction mediated by interferon-induced transmembrane protein 2 (IFITM2) and a pronounced infection enhancement by IFITM3. Furthermore, the P681H mutation is essential for resistance to IFN-β and context-dependent resistance to IFITMs in the alpha S. P681H reduces dependence on endosomal cathepsins, consistent with enhanced cell surface entry. However, reversion of H681 does not reduce cleaved spike incorporation into particles, indicating that it exerts its effect on entry and IFN-β downstream of furin cleavage. Overall, we suggest that, in addition to adaptive immune escape, mutations associated with VOC may well also confer a replication and/or transmission advantage through adaptation to resist innate immune mechanisms.
MeSH term(s)	Humans ; Spike Glycoprotein, Coronavirus/genetics ; Spike Glycoprotein, Coronavirus/metabolism ; SARS-CoV-2/genetics ; SARS-CoV-2/metabolism ; Furin/metabolism ; Interferon Type I/genetics ; Interferon Type I/metabolism ; COVID-19 ; Cell Line ; Mutation ; Membrane Proteins/metabolism ; RNA-Binding Proteins/metabolism
Chemical Substances	spike protein, SARS-CoV-2 ; Spike Glycoprotein, Coronavirus ; Furin (EC 3.4.21.75) ; Interferon Type I ; IFITM2 protein, human ; Membrane Proteins ; IFITM3 protein, human ; RNA-Binding Proteins
Language	English
Publishing date	2022-11-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/jvi.01250-22
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Article ; Online: The Polybasic Cleavage Site in SARS-CoV-2 Spike Modulates Viral Sensitivity to Type I Interferon and IFITM2.

Winstone, Helena / Lista, Maria Jose / Reid, Alisha C / Bouton, Clement / Pickering, Suzanne / Galao, Rui Pedro / Kerridge, Claire / Doores, Katie J / Swanson, Chad M / Neil, Stuart J D

Journal of virology

2021 Volume 95, Issue 9

Abstract: The cellular entry of severe acute respiratory syndrome-associated coronaviruses types 1 and 2 (SARS-CoV-1 and -2) requires sequential protease processing of the viral spike glycoprotein. The presence of a polybasic cleavage site in SARS-CoV-2 spike at ... ...

Abstract	The cellular entry of severe acute respiratory syndrome-associated coronaviruses types 1 and 2 (SARS-CoV-1 and -2) requires sequential protease processing of the viral spike glycoprotein. The presence of a polybasic cleavage site in SARS-CoV-2 spike at the S1/S2 boundary has been suggested to be a factor in the increased transmissibility of SARS-CoV-2 compared to SARS-CoV-1 by facilitating maturation of the spike precursor by furin-like proteases in the producer cells rather than endosomal cathepsins in the target. We investigate the relevance of the polybasic cleavage site in the route of entry of SARS-CoV-2 and the consequences this has for sensitivity to interferons (IFNs) and, more specifically, the IFN-induced transmembrane (IFITM) protein family that inhibit entry of diverse enveloped viruses. We found that SARS-CoV-2 is restricted predominantly by IFITM2, rather than IFITM3, and the degree of this restriction is governed by route of viral entry. Importantly, removal of the cleavage site in the spike protein renders SARS-CoV-2 entry highly pH and cathepsin dependent in late endosomes, where, like SARS-CoV-1 spike, it is more sensitive to IFITM2 restriction. Furthermore, we found that potent inhibition of SARS-CoV-2 replication by type I but not type II IFNs is alleviated by targeted depletion of IFITM2 expression. We propose that the polybasic cleavage site allows SARS-CoV-2 to mediate viral entry in a pH-independent manner, in part to mitigate against IFITM-mediated restriction and promote replication and transmission. This suggests that therapeutic strategies that target furin-mediated cleavage of SARS-CoV-2 spike may reduce viral replication through the activity of type I IFNs.
MeSH term(s)	A549 Cells ; Humans ; Interferon Type I/genetics ; Interferon Type I/metabolism ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Proteolysis ; SARS-CoV-2/physiology ; Spike Glycoprotein, Coronavirus/genetics ; Spike Glycoprotein, Coronavirus/metabolism ; Virus Internalization ; Virus Replication
Chemical Substances	IFITM2 protein, human ; Interferon Type I ; Membrane Proteins ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2021-04-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.02422-20
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Article ; Online: TMPRSS2 promotes SARS-CoV-2 evasion from NCOA7-mediated restriction.

Khan, Hataf / Winstone, Helena / Jimenez-Guardeño, Jose M / Graham, Carl / Doores, Katie J / Goujon, Caroline / Matthews, David A / Davidson, Andrew D / Rihn, Suzannah J / Palmarini, Massimo / Neil, Stuart J D / Malim, Michael H

PLoS pathogens

2021 Volume 17, Issue 11, Page(s) e1009820

Abstract: Interferons play a critical role in regulating host immune responses to SARS-CoV-2, but the interferon (IFN)-stimulated gene (ISG) effectors that inhibit SARS-CoV-2 are not well characterized. The IFN-inducible short isoform of human nuclear receptor ... ...

Abstract	Interferons play a critical role in regulating host immune responses to SARS-CoV-2, but the interferon (IFN)-stimulated gene (ISG) effectors that inhibit SARS-CoV-2 are not well characterized. The IFN-inducible short isoform of human nuclear receptor coactivator 7 (NCOA7) inhibits endocytic virus entry, interacts with the vacuolar ATPase, and promotes endo-lysosomal vesicle acidification and lysosomal protease activity. Here, we used ectopic expression and gene knockout to demonstrate that NCOA7 inhibits infection by SARS-CoV-2 as well as by lentivirus particles pseudotyped with SARS-CoV-2 Spike in lung epithelial cells. Infection with the highly pathogenic, SARS-CoV-1 and MERS-CoV, or seasonal, HCoV-229E and HCoV-NL63, coronavirus Spike-pseudotyped viruses was also inhibited by NCOA7. Importantly, either overexpression of TMPRSS2, which promotes plasma membrane fusion versus endosomal fusion of SARS-CoV-2, or removal of Spike's polybasic furin cleavage site rendered SARS-CoV-2 less sensitive to NCOA7 restriction. Collectively, our data indicate that furin cleavage sensitizes SARS-CoV-2 Spike to the antiviral consequences of endosomal acidification by NCOA7, and suggest that the acquisition of furin cleavage may have favoured the co-option of cell surface TMPRSS proteases as a strategy to evade the suppressive effects of IFN-induced endo-lysosomal dysregulation on virus infection.
MeSH term(s)	COVID-19/virology ; Cell Line ; Endosomes/metabolism ; Furin/genetics ; Furin/metabolism ; Gene Expression ; Humans ; Immune Evasion ; Interferons/metabolism ; Lysosomes/enzymology ; Nuclear Receptor Coactivators/genetics ; Nuclear Receptor Coactivators/metabolism ; Protein Isoforms ; Proteolysis ; SARS-CoV-2/physiology ; Serine Endopeptidases/genetics ; Serine Endopeptidases/metabolism ; Spike Glycoprotein, Coronavirus/metabolism ; Viral Pseudotyping ; Virus Internalization
Chemical Substances	NCOA7 protein, human ; Nuclear Receptor Coactivators ; Protein Isoforms ; Spike Glycoprotein, Coronavirus ; Interferons (9008-11-1) ; Serine Endopeptidases (EC 3.4.21.-) ; TMPRSS2 protein, human (EC 3.4.21.-) ; FURIN protein, human (EC 3.4.21.75) ; Furin (EC 3.4.21.75)
Language	English
Publishing date	2021-11-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; 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.1009820
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: The P681H mutation in the Spike glycoprotein escapes IFITM restriction and is necessary for type I interferon resistance in the SARS-CoV-2 alpha variant

Lista, Maria Jose / Winstone, Helena / Wilson, Harry / Dyer, Adam / Pickering, Suzanne / Galao, Rui Pedro / De Lorenzo, Giuditta / Cowton, Vanessa / Furnon, Wilhelm / Suárez, Nicolás M. / Orton, Richard / Palmirini, Massimo / Patel, Arvind H. / Snell, Luke B / Nebbia, Gaia / Swanson, Chad M / Neil, Stuart J

bioRxiv

Abstract: The appearance of new dominant variants of concern (VOCs) of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) threatens the global response to the COVID-19 pandemic. Of these, the alpha variant (also known as B.1.1.7) that appeared ... ...

Abstract	The appearance of new dominant variants of concern (VOCs) of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) threatens the global response to the COVID-19 pandemic. Of these, the alpha variant (also known as B.1.1.7) that appeared initially in the UK became the dominant variant in much of Europe and North America in the first half of 2021. The Spike (S) glycoprotein of alpha acquired seven mutations and two deletions compared to the ancestral virus, including the P681H mutation in the polybasic cleavage site that has been suggested to enhance S cleavage. Here, we show that the alpha S protein confers a level of resistance to the effects of interferon-b (IFNb) in human lung epithelial cells. This correlates with resistance to an entry restriction mediated by interferon-induced transmembrane protein 2 (IFITM2) and a pronounced infection enhancement by IFITM3. Furthermore, the P681H mutation is essential for resistance to IFNb and context-dependent resistance to IFITMs in the alpha S. However, while this appears to confer changes in sensitivity to endosomal protease inhibition consistent with enhanced cell-surface entry, its reversion does not reduce cleaved S incorporation into particles, indicating a role downstream of furin cleavage. Overall, we suggest that, in addition to adaptive immune escape, mutations associated with VOCs may well also confer replication and/or transmission advantage through adaptation to resist innate immune mechanisms.
Keywords	covid19
Language	English
Publishing date	2022-08-15
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2022.08.11.503706
Database	COVID19

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Article ; Online: TMPRSS2 promotes SARS-CoV-2 evasion from NCOA7-mediated restriction.

Hataf Khan / Helena Winstone / Jose M Jimenez-Guardeño / Carl Graham / Katie J Doores / Caroline Goujon / David A Matthews / Andrew D Davidson / Suzannah J Rihn / Massimo Palmarini / Stuart J D Neil / Michael H Malim

PLoS Pathogens, Vol 17, Iss 11, p e

2021 Volume 1009820

Abstract	Interferons play a critical role in regulating host immune responses to SARS-CoV-2, but the interferon (IFN)-stimulated gene (ISG) effectors that inhibit SARS-CoV-2 are not well characterized. The IFN-inducible short isoform of human nuclear receptor coactivator 7 (NCOA7) inhibits endocytic virus entry, interacts with the vacuolar ATPase, and promotes endo-lysosomal vesicle acidification and lysosomal protease activity. Here, we used ectopic expression and gene knockout to demonstrate that NCOA7 inhibits infection by SARS-CoV-2 as well as by lentivirus particles pseudotyped with SARS-CoV-2 Spike in lung epithelial cells. Infection with the highly pathogenic, SARS-CoV-1 and MERS-CoV, or seasonal, HCoV-229E and HCoV-NL63, coronavirus Spike-pseudotyped viruses was also inhibited by NCOA7. Importantly, either overexpression of TMPRSS2, which promotes plasma membrane fusion versus endosomal fusion of SARS-CoV-2, or removal of Spike's polybasic furin cleavage site rendered SARS-CoV-2 less sensitive to NCOA7 restriction. Collectively, our data indicate that furin cleavage sensitizes SARS-CoV-2 Spike to the antiviral consequences of endosomal acidification by NCOA7, and suggest that the acquisition of furin cleavage may have favoured the co-option of cell surface TMPRSS proteases as a strategy to evade the suppressive effects of IFN-induced endo-lysosomal dysregulation on virus infection.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Subject code	570 ; 572
Language	English
Publishing date	2021-11-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The P681H mutation in the Spike glycoprotein confers Type I interferon resistance in the SARS-CoV-2 alpha (B.1.1.7) variant

Lista, Maria Jose / Winstone, Helena / Wilson, Harry / Dyer, Adam / Pickering, Suzanne / Galao, Rui Pedro / De Lorenzo, Giudetta / Cowton, Vanessa / Furnon, Wilhelm / Suarez, Nicolas M / Orton, Richard / Palmarini, Massimo / Patel, Arvind H / Snell, Luke B / Nebbia, Gaia / Swanson, Chad M / Neil, Stuart

bioRxiv

Abstract: Variants of concern (VOCs) of severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2) threaten the global response to the COVID-19 pandemic. The alpha (B.1.1.7) variant appeared in the UK became dominant in Europe and North America in early ... ...

Abstract	Variants of concern (VOCs) of severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2) threaten the global response to the COVID-19 pandemic. The alpha (B.1.1.7) variant appeared in the UK became dominant in Europe and North America in early 2021. The Spike glycoprotein of alpha has acquired a number mutations including the P681H mutation in the polybasic cleavage site that has been suggested to enhance Spike cleavage. Here, we show that the alpha Spike protein confers a level of resistance to the effects of interferon-β (IFNβ) in lung epithelial cells. This correlates with resistance to restriction mediated by interferon-induced transmembrane protein-2 (IFITM2) and a pronounced infection enhancement by IFITM3. Furthermore, the P681H mutation is necessary for comparative resistance to IFNβ in a molecularly cloned SARS-CoV-2 encoding alpha Spike. Overall, we suggest that in addition to adaptive immune escape, mutations associated with VOCs also confer replication advantage through adaptation to resist innate immunity.
Keywords	covid19
Language	English
Publishing date	2021-11-10
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2021.11.09.467693
Database	COVID19

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Article: Impact of the B.1.1.7 variant on neutralizing monoclonal antibodies recognizing diverse epitopes on SARS-CoV-2 Spike.

Graham, Carl / Seow, Jeffrey / Huettner, Isabella / Khan, Hataf / Kouphou, Neophytos / Acors, Sam / Winstone, Helena / Pickering, Suzanne / Galao, Rui Pedro / Lista, Maria Jose / Jimenez-Guardeno, Jose M / Laing, Adam G / Wu, Yin / Joseph, Magdalene / Muir, Luke / Ng, Weng M / Duyvesteyn, Helen M E / Zhao, Yuguang / Bowden, Thomas A /

Shankar-Hari, Manu / Rosa, Annachiara / Cherepanov, Peter / McCoy, Laura E / Hayday, Adrian C / Neil, Stuart J D / Malim, Michael H / Doores, Katie J

bioRxiv : the preprint server for biology

2021

Abstract: The interaction of the SARS-CoV-2 Spike receptor binding domain (RBD) with the ACE2 receptor on host cells is essential for viral entry. RBD is the dominant target for neutralizing antibodies and several neutralizing epitopes on RBD have been molecularly ...

Abstract	The interaction of the SARS-CoV-2 Spike receptor binding domain (RBD) with the ACE2 receptor on host cells is essential for viral entry. RBD is the dominant target for neutralizing antibodies and several neutralizing epitopes on RBD have been molecularly characterized. Analysis of circulating SARS-CoV-2 variants has revealed mutations arising in the RBD, the N-terminal domain (NTD) and S2 subunits of Spike. To fully understand how these mutations affect the antigenicity of Spike, we have isolated and characterized neutralizing antibodies targeting epitopes beyond the already identified RBD epitopes. Using recombinant Spike as a sorting bait, we isolated >100 Spike-reactive monoclonal antibodies from SARS-CoV-2 infected individuals. ≈45% showed neutralizing activity of which ≈20% were NTD-specific. None of the S2-specific antibodies showed neutralizing activity. Competition ELISA revealed that NTD-specific mAbs formed two distinct groups: the first group was highly potent against infectious virus, whereas the second was less potent and displayed glycan-dependant neutralization activity. Importantly, mutations present in B.1.1.7 Spike frequently conferred resistance to neutralization by the NTD-specific neutralizing antibodies. This work demonstrates that neutralizing antibodies targeting subdominant epitopes need to be considered when investigating antigenic drift in emerging variants.
Language	English
Publishing date	2021-02-03
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.02.03.429355
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Article: Antibody longevity and cross-neutralizing activity following SARS-CoV-2 wave 1 and B.1.1.7 infections.

Dupont, Liane / Snell, Luke B / Graham, Carl / Seow, Jeffrey / Merrick, Blair / Lechmere, Thomas / Hallett, Sadie R / Charalampous, Themoula / Alcolea-Medina, Adela / Huettner, Isabella / Maguire, Thomas J A / Acors, Sam / Almeida, Nathalia / Cox, Daniel / Dickenson, Ruth E / Galao, Rui Pedro / Jimenez-Guardeño, Jose M / Kouphou, Neophytos / Lista, Marie Jose /

Pickering, Suzanne / Ortega-Prieto, Ana Maria / Wilson, Harry / Winstone, Helena / Fairhead, Cassandra / Su, Jia / Nebbia, Gaia / Batra, Rahul / Neil, Stuart / Shankar-Hari, Manu / Edgeworth, Jonathan D / Malim, Michael H / Doores, Katie J

medRxiv : the preprint server for health sciences

2021

Abstract: As SARS-CoV-2 variants continue to emerge globally, a major challenge for COVID-19 vaccination is the generation of a durable antibody response with cross-neutralizing activity against both current and newly emerging viral variants. Cross-neutralizing ... ...

Abstract	As SARS-CoV-2 variants continue to emerge globally, a major challenge for COVID-19 vaccination is the generation of a durable antibody response with cross-neutralizing activity against both current and newly emerging viral variants. Cross-neutralizing activity against major variants of concern (B.1.1.7, P.1 and B.1.351) has been observed following vaccination, albeit at a reduced potency, but whether vaccines based on the Spike glycoprotein of these viral variants will produce a superior cross-neutralizing antibody response has not been fully investigated. Here, we used sera from individuals infected in wave 1 in the UK to study the long-term cross-neutralization up to 10 months post onset of symptoms (POS), as well as sera from individuals infected with the B.1.1.7 variant to compare cross-neutralizing activity profiles. We show that neutralizing antibodies with cross-neutralizing activity can be detected from wave 1 up to 10 months POS. Although neutralization of B.1.1.7 and B.1.351 is lower, the difference in neutralization potency decreases at later timepoints suggesting continued antibody maturation and improved tolerance to Spike mutations. Interestingly, we found that B.1.1.7 infection also generates a cross-neutralizing antibody response, which, although still less potent against B.1.351, can neutralize parental wave 1 virus to a similar degree as B.1.1.7. These findings have implications for the optimization of vaccines that protect against newly emerging viral variants.
Language	English
Publishing date	2021-06-08
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.06.07.21258351
Database	MEDical Literature Analysis and Retrieval System OnLINE

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