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Article ; Online: SARS-CoV-2 vaccine ChAdOx1 nCoV-19 infection of human cell lines reveals low levels of viral backbone gene transcription alongside very high levels of SARS-CoV-2 S glycoprotein gene transcription

Abdulaziz Almuqrin / Andrew D. Davidson / Maia Kavanagh Williamson / Philip A. Lewis / Kate J. Heesom / Susan Morris / Sarah C. Gilbert / David A. Matthews

Genome Medicine, Vol 13, Iss 1, Pp 1-

2021 Volume 17

Abstract: Abstract Background ChAdOx1 nCoV-19 is a recombinant adenovirus vaccine against SARS-CoV-2 that has passed phase III clinical trials and is now in use across the globe. Although replication-defective in normal cells, 28 kbp of adenovirus genes is ... ...

Abstract	Abstract Background ChAdOx1 nCoV-19 is a recombinant adenovirus vaccine against SARS-CoV-2 that has passed phase III clinical trials and is now in use across the globe. Although replication-defective in normal cells, 28 kbp of adenovirus genes is delivered to the cell nucleus alongside the SARS-CoV-2 S glycoprotein gene. Methods We used direct RNA sequencing to analyse transcript expression from the ChAdOx1 nCoV-19 genome in human MRC-5 and A549 cell lines that are non-permissive for vector replication alongside the replication permissive cell line, HEK293. In addition, we used quantitative proteomics to study over time the proteome and phosphoproteome of A549 and MRC5 cells infected with the ChAdOx1 nCoV-19 vaccine. Results The expected SARS-CoV-2 S coding transcript dominated in all cell lines. We also detected rare S transcripts with aberrant splice patterns or polyadenylation site usage. Adenovirus vector transcripts were almost absent in MRC-5 cells, but in A549 cells, there was a broader repertoire of adenoviral gene expression at very low levels. Proteomically, in addition to S glycoprotein, we detected multiple adenovirus proteins in A549 cells compared to just one in MRC5 cells. Conclusions Overall, the ChAdOx1 nCoV-19 vaccine’s transcriptomic and proteomic repertoire in cell culture is as expected. The combined transcriptomic and proteomics approaches provide a detailed insight into the behaviour of this important class of vaccine using state-of-the-art techniques and illustrate the potential of this technique to inform future viral vaccine vector design.
Keywords	Medicine ; R ; Genetics ; QH426-470
Subject code	570
Language	English
Publishing date	2021-03-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Analysis of an Ebola virus disease survivor whose host and viral markers were predictive of death indicates the effectiveness of medical countermeasures and supportive care

Andrew Bosworth / Natasha Y. Rickett / Xiaofeng Dong / Lisa F. P. Ng / Isabel García-Dorival / David A. Matthews / Tom Fletcher / Michael Jacobs / Emma C. Thomson / Miles W. Carroll / Julian A. Hiscox

Genome Medicine, Vol 13, Iss 1, Pp 1-

2021 Volume 18

Abstract: Abstract Background Ebola virus disease (EVD) is an often-fatal infection where the effectiveness of medical countermeasures is uncertain. During the West African outbreak (2013–2016), several patients were treated with different types of anti-viral ... ...

Abstract	Abstract Background Ebola virus disease (EVD) is an often-fatal infection where the effectiveness of medical countermeasures is uncertain. During the West African outbreak (2013–2016), several patients were treated with different types of anti-viral therapies including monoclonal antibody-based cocktails that had the potential to neutralise Ebola virus (EBOV). However, at the time, the efficacy of these therapies was uncertain. Given the scale of the outbreak, several clinical phenotypes came to the forefront including the ability of the same virus to cause recrudescence in the same patient—perhaps through persisting in immune privileged sites. Several key questions remained including establishing if monoclonal antibody therapy was effective in humans with severe EVD, whether virus escape mutants were selected during treatment, and what is the potential mechanism(s) of persistence. This was made possible through longitudinal samples taken from a UK patient with EVD. Methods Several different sample types, plasma and cerebrospinal fluid, were collected and sequenced using Illumina-based RNAseq. Sequence reads were mapped both to EBOV and the human genome and differential gene expression analysis used to identify changes in the abundance of gene transcripts as infection progressed. Digital Cell Quantitation analysis was used to predict the immune phenotype in samples derived from blood. Results The findings were compared to equivalent data from West African patients. The study found that both virus and host markers were predictive of a fatal outcome. This suggested that the extensive supportive care, and most likely the application of the medical countermeasure ZMab (a monoclonal antibody cocktail), contributed to survival of the UK patient. The switch from progression to a ‘fatal’ outcome to a ‘survival’ outcome could be seen in both the viral and host markers. The UK patient also suffered a recrudescence infection 10 months after the initial infection. Analysis of the sequencing data indicated that the virus ...
Keywords	Medicine ; R ; Genetics ; QH426-470
Subject code	570 ; 616
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The SARS-CoV-2 protein ORF3c is a mitochondrial modulator of innate immunity

iScience, Vol 26, Iss 11, Pp 108080- (2023)

2023

Abstract: Summary: The SARS-CoV-2 genome encodes a multitude of accessory proteins. Using comparative genomic approaches, an additional accessory protein, ORF3c, has been predicted to be encoded within the ORF3a sgmRNA. Expression of ORF3c during infection has ... ...

Abstract	Summary: The SARS-CoV-2 genome encodes a multitude of accessory proteins. Using comparative genomic approaches, an additional accessory protein, ORF3c, has been predicted to be encoded within the ORF3a sgmRNA. Expression of ORF3c during infection has been confirmed independently by ribosome profiling. Despite ORF3c also being present in the 2002–2003 SARS-CoV, its function has remained unexplored. Here we show that ORF3c localizes to mitochondria, where it inhibits innate immunity by restricting IFN-β production, but not NF-κB activation or JAK-STAT signaling downstream of type I IFN stimulation. We find that ORF3c is inhibitory after stimulation with cytoplasmic RNA helicases RIG-I or MDA5 or adaptor protein MAVS, but not after TRIF, TBK1 or phospho-IRF3 stimulation. ORF3c co-immunoprecipitates with the antiviral proteins MAVS and PGAM5 and induces MAVS cleavage by caspase-3. Together, these data provide insight into an uncharacterized mechanism of innate immune evasion by this important human pathogen.
Keywords	Molecular biology ; Immunology ; Microbiology ; Proteomics ; Science ; Q
Subject code	570
Language	English
Publishing date	2023-11-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Characterisation of the transcriptome and proteome of SARS-CoV-2 reveals a cell passage induced in-frame deletion of the furin-like cleavage site from the spike glycoprotein

Andrew D. Davidson / Maia Kavanagh Williamson / Sebastian Lewis / Deborah Shoemark / Miles W. Carroll / Kate J. Heesom / Maria Zambon / Joanna Ellis / Philip A. Lewis / Julian A. Hiscox / David A. Matthews

Genome Medicine, Vol 12, Iss 1, Pp 1-

2020 Volume 15

Abstract: Abstract Background SARS-CoV-2 is a recently emerged respiratory pathogen that has significantly impacted global human health. We wanted to rapidly characterise the transcriptomic, proteomic and phosphoproteomic landscape of this novel coronavirus to ... ...

Abstract	Abstract Background SARS-CoV-2 is a recently emerged respiratory pathogen that has significantly impacted global human health. We wanted to rapidly characterise the transcriptomic, proteomic and phosphoproteomic landscape of this novel coronavirus to provide a fundamental description of the virus’s genomic and proteomic potential. Methods We used direct RNA sequencing to determine the transcriptome of SARS-CoV-2 grown in Vero E6 cells which is widely used to propagate the novel coronavirus. The viral transcriptome was analysed using a recently developed ORF-centric pipeline. Allied to this, we used tandem mass spectrometry to investigate the proteome and phosphoproteome of the same virally infected cells. Results Our integrated analysis revealed that the viral transcripts (i.e. subgenomic mRNAs) generally fitted the expected transcription model for coronaviruses. Importantly, a 24 nt in-frame deletion was detected in over half of the subgenomic mRNAs encoding the spike (S) glycoprotein and was predicted to remove a proposed furin cleavage site from the S glycoprotein. Tandem mass spectrometry identified over 500 viral peptides and 44 phosphopeptides in virus-infected cells, covering almost all proteins predicted to be encoded by the SARS-CoV-2 genome, including peptides unique to the deleted variant of the S glycoprotein. Conclusions Detection of an apparently viable deletion in the furin cleavage site of the S glycoprotein, a leading vaccine target, shows that this and other regions of SARS-CoV-2 proteins may readily mutate. The furin site directs cleavage of the S glycoprotein into functional subunits during virus entry or exit and likely contributes strongly to the pathogenesis and zoonosis of this virus. Our data emphasises that the viral genome sequence should be carefully monitored during the growth of viral stocks for research, animal challenge models and, potentially, in clinical samples. Such variations may result in different levels of virulence, morbidity and mortality.
Keywords	Medicine ; R ; Genetics ; QH426-470 ; covid19
Subject code	570
Language	English
Publishing date	2020-07-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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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 ... ...

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: Structural insights in cell-type specific evolution of intra-host diversity by SARS-CoV-2

Kapil Gupta / Christine Toelzer / Maia Kavanagh Williamson / Deborah K. Shoemark / A. Sofia F. Oliveira / David A. Matthews / Abdulaziz Almuqrin / Oskar Staufer / Sathish K. N. Yadav / Ufuk Borucu / Frederic Garzoni / Daniel Fitzgerald / Joachim Spatz / Adrian J. Mulholland / Andrew D. Davidson / Christiane Schaffitzel / Imre Berger

Nature Communications, Vol 13, Iss 1, Pp 1-

2022 Volume 12

Abstract: BriSΔ, a SARS-CoV-2 variant from clinical isolate hCoV/England/02/2020, comprises a deletion in a spike cleavage site. The structure and molecular dynamics of this spike provides mechanistic insights into how the deletion modulates virus infectivity. ...

Abstract	BriSΔ, a SARS-CoV-2 variant from clinical isolate hCoV/England/02/2020, comprises a deletion in a spike cleavage site. The structure and molecular dynamics of this spike provides mechanistic insights into how the deletion modulates virus infectivity.
Keywords	Science ; Q
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: High-throughput quantitative proteomic analysis of dengue virus type 2 infected A549 cells.

Han-Chen Chiu / Holger Hannemann / Kate J Heesom / David A Matthews / Andrew D Davidson

PLoS ONE, Vol 9, Iss 3, p e

2014 Volume 93305

Abstract: Disease caused by dengue virus is a global health concern with up to 390 million individuals infected annually worldwide. There are no vaccines or antiviral compounds available to either prevent or treat dengue disease which may be fatal. To increase our ...

Abstract	Disease caused by dengue virus is a global health concern with up to 390 million individuals infected annually worldwide. There are no vaccines or antiviral compounds available to either prevent or treat dengue disease which may be fatal. To increase our understanding of the interaction of dengue virus with the host cell, we analyzed changes in the proteome of human A549 cells in response to dengue virus type 2 infection using stable isotope labelling in cell culture (SILAC) in combination with high-throughput mass spectrometry (MS). Mock and infected A549 cells were fractionated into nuclear and cytoplasmic extracts before analysis to identify proteins that redistribute between cellular compartments during infection and reduce the complexity of the analysis. We identified and quantified 3098 and 2115 proteins in the cytoplasmic and nuclear fractions respectively. Proteins that showed a significant alteration in amount during infection were examined using gene enrichment, pathway and network analysis tools. The analyses revealed that dengue virus infection modulated the amounts of proteins involved in the interferon and unfolded protein responses, lipid metabolism and the cell cycle. The SILAC-MS results were validated for a select number of proteins over a time course of infection by Western blotting and immunofluorescence microscopy. Our study demonstrates for the first time the power of SILAC-MS for identifying and quantifying novel changes in cellular protein amounts in response to dengue virus infection.
Keywords	Medicine ; R ; Science ; Q
Subject code	570
Language	English
Publishing date	2014-01-01T00:00:00Z
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: Variation around the dominant viral genome sequence contributes to viral load and outcome in patients with Ebola virus disease

Xiaofeng Dong / Jordana Munoz-Basagoiti / Natasha Y. Rickett / Georgios Pollakis / William A. Paxton / Stephan Günther / Romy Kerber / Lisa F. P. Ng / Michael J. Elmore / N’faly Magassouba / Miles W. Carroll / David A. Matthews / Julian A. Hiscox

Genome Biology, Vol 21, Iss 1, Pp 1-

2020 Volume 20

Abstract: Abstract Background Viral load is a major contributor to outcome in patients with Ebola virus disease (EVD), with high values leading to a fatal outcome. Evidence from the 2013–2016 Ebola virus (EBOV) outbreak indicated that different genotypes of the ... ...

Abstract	Abstract Background Viral load is a major contributor to outcome in patients with Ebola virus disease (EVD), with high values leading to a fatal outcome. Evidence from the 2013–2016 Ebola virus (EBOV) outbreak indicated that different genotypes of the virus can have different phenotypes in patients. Additionally, due to the error-prone nature of viral RNA synthesis in an individual patient, the EBOV genome exists around a dominant viral genome sequence. The minor variants within a patient may contribute to the overall phenotype in terms of viral protein function. To investigate the effects of these minor variants, blood samples from patients with acute EVD were deeply sequenced. Results We examine the minor variant frequency between patients with acute EVD who survived infection with those who died. Non-synonymous differences in viral proteins were identified that have implications for viral protein function. The greatest frequency of substitution was identified at three codon sites in the L gene—which encodes the viral RNA-dependent RNA polymerase (RdRp). Recapitulating this in an assay for virus replication, these substitutions result in aberrant viral RNA synthesis and correlate with patient outcome. Conclusions Together, these findings support the notion that in patients who survived EVD, in some cases, the genetic variability of the virus resulted in deleterious mutations that affected viral protein function, leading to reduced viral load. Such mutations may also lead to persistent strains of the virus and be associated with recrudescent infections.
Keywords	Ebola virus ; Ebola virus disease ; Virus genetics ; Evolution ; Patient outcome ; Biology (General) ; QH301-705.5 ; Genetics ; QH426-470
Subject code	616
Language	English
Publishing date	2020-09-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Identification of Epstein-Barr Virus Replication Proteins in Burkitt’s Lymphoma Cells

Chris Traylen / Sharada Ramasubramanyan / Jianmin Zuo / Martin Rowe / Rajaei Almohammad / Kate Heesom / Steve M. M. Sweet / David A. Matthews / Alison J. Sinclair

Pathogens, Vol 4, Iss 4, Pp 739-

2015 Volume 751

Abstract: The working model to describe the mechanisms used to replicate the cancer-associated virus Epstein-Barr virus (EBV) is partly derived from comparisons with other members of the Herpes virus family. Many genes within the EBV genome are homologous across ... ...

Abstract	The working model to describe the mechanisms used to replicate the cancer-associated virus Epstein-Barr virus (EBV) is partly derived from comparisons with other members of the Herpes virus family. Many genes within the EBV genome are homologous across the herpes virus family. Published transcriptome data for the EBV genome during its lytic replication cycle show extensive transcription, but the identification of the proteins is limited. We have taken a global proteomics approach to identify viral proteins that are expressed during the EBV lytic replication cycle. We combined an enrichment method to isolate cells undergoing EBV lytic replication with SILAC-labeling coupled to mass-spectrometry and identified viral and host proteins expressed during the OPEN ACCESS Pathogens 2015, 4 740 EBV lytic replication cycle. Amongst the most frequently identified viral proteins are two components of the DNA replication machinery, the single strand DNA binding protein BALF2, DNA polymerase accessory protein BMRF1 and both subunits of the viral ribonucleoside-diphosphate reductase enzyme (BORF2 and BaRF1). An additional 42 EBV lytic cycle proteins were also detected. This provides proteomic identification for many EBV lytic replication cycle proteins and also identifies post-translational modifications.
Keywords	virus ; cancer ; replication ; proteome ; herpes ; Epstein-Barr ; Medicine ; R
Subject code	570
Language	English
Publishing date	2015-10-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Changes in the long-term supply of mercury species to the upper mixed waters of a recovering lake

Todorova, Svetoslava G / Charles T. Driscoll / David A. Matthews / Dimitar L. Todorov / Stephanie Gindlesperger / Steven W. Effler / Susan O'Donnell

Environmental pollution. 2014 Feb., v. 185

2014

Abstract: We quantified internal processes that supply methylmercury from hypolimnetic reducing zones to the upper waters of a Hg-contaminated lake, Onondaga Lake, NY, USA. Diffusive transport continuously supplied methylmercury to the epilimnion under summer ... ...

Abstract	We quantified internal processes that supply methylmercury from hypolimnetic reducing zones to the upper waters of a Hg-contaminated lake, Onondaga Lake, NY, USA. Diffusive transport continuously supplied methylmercury to the epilimnion under summer stratification, while fall mixing resulted in a pulsed release of methylmercury to the upper mixed waters. These processes were the main internal sources of methylmercury to the epilimnion, and together almost equaled the total external supply. The wind-driven entrainment represented an additional stochastic internal supply of methylmercury of approximately 9% in 2006. Considering more than 15 years of data, we estimate 1.8 wind-driven events occur per year. The mass of methylmercury inputs to the epilimnion exceeded the measured increase, suggesting that loss processes are important in regulating methylmercury accumulation. The relative contribution of internal sources of methylmercury to the epilimnion has decreased in recent years, shifting the importance to the external inputs.
Keywords	lakes ; mercury ; methylmercury compounds ; mixing ; summer ; United States
Language	English
Dates of publication	2014-02
Size	p. 314-321.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	280652-6
ISSN	1873-6424 ; 0013-9327 ; 0269-7491
ISSN (online)	1873-6424
ISSN	0013-9327 ; 0269-7491
DOI	10.1016/j.envpol.2013.11.005
Database	NAL-Catalogue (AGRICOLA)

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