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Article ; Online: The clinical correlates of vaccine-induced immune thrombotic thrombocytopenia after immunisation with adenovirus vector-based SARS-CoV-2 vaccines.

Gaunt, Eleanor R / Mabbott, Neil A

Immunotherapy advances

2021 Volume 1, Issue 1, Page(s) ltab019

Abstract: We are at a critical stage in the COVID-19 pandemic where vaccinations are being rolled out globally, in a race against time to get ahead of the SARS-CoV-2 coronavirus and the emergence of more highly transmissible variants. A range of vaccines have been ...

Abstract	We are at a critical stage in the COVID-19 pandemic where vaccinations are being rolled out globally, in a race against time to get ahead of the SARS-CoV-2 coronavirus and the emergence of more highly transmissible variants. A range of vaccines have been created and received either emergency approval or full licensure. To attain the upper hand, maximum vaccine synthesis, deployment, and uptake as rapidly as possible is essential. However, vaccine uptake, particularly in younger adults is dropping, at least in part fuelled by reports of rare complications associated with specific vaccines. This review considers how vaccination with adenovirus vector-based vaccines against the SARS-CoV-2 coronavirus might cause rare cases of thrombosis and thrombocytopenia in some recipients. A thorough understanding of the underlying cellular and molecular mechanisms that mediate this syndrome may help to identify methods to prevent these very rare, but serious side effects. This will also help facilitate the identification of those at highest risk from these outcomes, so that we can work towards a stratified approach to vaccine deployment to mitigate these risks.
Language	English
Publishing date	2021-08-17
Publishing country	England
Document type	Journal Article ; Review
ISSN	2732-4303
ISSN (online)	2732-4303
DOI	10.1093/immadv/ltab019
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Article ; Online: Compositional biases in RNA viruses: Causes, consequences and applications.

Gaunt, Eleanor R / Digard, Paul

Wiley interdisciplinary reviews. RNA

2021 Volume 13, Issue 2, Page(s) e1679

Abstract: If each of the four nucleotides were represented equally in the genomes of viruses and the hosts they infect, each base would occur at a frequency of 25%. However, this is not observed in nature. Similarly, the order of nucleotides is not random (e.g., ... ...

Abstract	If each of the four nucleotides were represented equally in the genomes of viruses and the hosts they infect, each base would occur at a frequency of 25%. However, this is not observed in nature. Similarly, the order of nucleotides is not random (e.g., in the human genome, guanine follows cytosine at a frequency of ~0.0125, or a quarter the number of times predicted by random representation). Codon usage and codon order are also nonrandom. Furthermore, nucleotide and codon biases vary between species. Such biases have various drivers, including cellular proteins that recognize specific patterns in nucleic acids, that once triggered, induce mutations or invoke intrinsic or innate immune responses. In this review we examine the types of compositional biases identified in viral genomes and current understanding of the evolutionary mechanisms underpinning these trends. Finally, we consider the potential for large scale synonymous recoding strategies to engineer RNA virus vaccines, including those with pandemic potential, such as influenza A virus and Severe Acute Respiratory Syndrome Coronavirus Virus 2. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Evolution and Genomics > Computational Analyses of RNA RNA Interactions with Proteins and Other Molecules > Protein-RNA Recognition.
MeSH term(s)	Bias ; Codon/genetics ; Evolution, Molecular ; Genome, Viral ; Humans ; Nucleotides ; RNA Viruses/genetics ; Viruses/genetics
Chemical Substances	Codon ; Nucleotides
Language	English
Publishing date	2021-06-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2634714-3
ISSN	1757-7012 ; 1757-7004
ISSN (online)	1757-7012
ISSN	1757-7004
DOI	10.1002/wrna.1679
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Article ; Online: 1 Cellular protein TTC4 and its cofactor HSP90 are pro-viral for bovine herpesvirus 1.

Thompson, Beth H / Sharp, Colin P / Dry, Inga R / Dalziel, Robert G / Gaunt, Eleanor R

Virus research

2022 Volume 321, Page(s) 198927

Abstract: Bovine Herpesvirus Type 1 (BoHV-1) infection causes infectious bovine rhinotracheitis and genital disease in cattle, with significant economic and welfare impacts. However, the role of cellular host factors during viral replication remains poorly ... ...

Abstract	Bovine Herpesvirus Type 1 (BoHV-1) infection causes infectious bovine rhinotracheitis and genital disease in cattle, with significant economic and welfare impacts. However, the role of cellular host factors during viral replication remains poorly characterised. A previously performed genome-wide CRISPR knockout screen identified pro- and antiviral host factors acting during BoHV-1 replication. Herein we validate a pro-viral role for a candidate from this screen: the cellular protein tetracopeptide repeat protein 4 (TTC4). We show that TTC4 transcript production is upregulated during BoHV-1 infection. Depletion of TTC4 protein impairs BoHV-1 protein production but does not reduce production of infectious virions, whereas overexpression of exogenous TTC4 results in a significant increase in production of infectious BoHV-1 virions. TTC4 itself is poorly characterized (especially in the context of virus infection), but is a known co-chaperone of heat shock protein 90 (HSP90). HSP90 has a well-characterized pro-viral role during the replication of diverse herpesviruses, and we therefore hypothesized that HSP90 is also pro-viral for BoHV-1. Drug-mediated inhibition of HSP90 using geldanamycin at sub-cytotoxic concentrations inhibited both BoHV-1 protein production and viral genome replication, indicating a pro-viral role for HSP90 during BoHV-1 infection. Our data demonstrates pro-viral roles for both TTC4 and HSP90 during BoHV-1 replication; possibly, interactions between these two proteins are required for optimal BoHV-1 replication, or the two proteins may have independent pro-viral roles.
MeSH term(s)	Animals ; Antiviral Agents/metabolism ; Cattle ; HSP90 Heat-Shock Proteins/genetics ; HSP90 Heat-Shock Proteins/metabolism ; Herpesviridae Infections/veterinary ; Herpesvirus 1, Bovine/physiology ; Infectious Bovine Rhinotracheitis ; Virus Replication/genetics
Chemical Substances	Antiviral Agents ; HSP90 Heat-Shock Proteins
Language	English
Publishing date	2022-09-11
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605780-9
ISSN	1872-7492 ; 0168-1702
ISSN (online)	1872-7492
ISSN	0168-1702
DOI	10.1016/j.virusres.2022.198927
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Article ; Online: Corrigendum: The molecular basis of differential host responses to avian influenza viruses in avian species with differing susceptibility.

Morris, Katrina M / Mishra, Anamika / Raut, Ashwin A / Gaunt, Eleanor R / Borowska, Dominika / Kuo, Richard I / Wang, Bo / Vijayakumar, Periyasamy / Chingtham, Santhalembi / Dutta, Rupam / Baillie, Kenneth / Digard, Paul / Vervelde, Lonneke / Burt, David W / Smith, Jacqueline

Frontiers in cellular and infection microbiology

2023 Volume 13, Page(s) 1194878

Abstract: This corrects the article DOI: 10.3389/fcimb.2023.1067993.]. ...

Abstract	[This corrects the article DOI: 10.3389/fcimb.2023.1067993.].
Language	English
Publishing date	2023-04-04
Publishing country	Switzerland
Document type	Published Erratum
ZDB-ID	2619676-1
ISSN	2235-2988 ; 2235-2988
ISSN (online)	2235-2988
ISSN	2235-2988
DOI	10.3389/fcimb.2023.1194878
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Article: 1 Cellular protein TTC4 and its cofactor HSP90 are pro-viral for bovine herpesvirus 1

Thompson, Beth H / Sharp, Colin P / Dry, Inga R / Dalziel, Robert G / Gaunt, Eleanor R

Virus research. 2022 Nov., v. 321

2022

Abstract	Bovine Herpesvirus Type 1 (BoHV-1) infection causes infectious bovine rhinotracheitis and genital disease in cattle, with significant economic and welfare impacts. However, the role of cellular host factors during viral replication remains poorly characterised. A previously performed genome-wide CRISPR knockout screen identified pro- and antiviral host factors acting during BoHV-1 replication. Herein we validate a pro-viral role for a candidate from this screen: the cellular protein tetracopeptide repeat protein 4 (TTC4). We show that TTC4 transcript production is upregulated during BoHV-1 infection. Depletion of TTC4 protein impairs BoHV-1 protein production but does not reduce production of infectious virions, whereas overexpression of exogenous TTC4 results in a significant increase in production of infectious BoHV-1 virions. TTC4 itself is poorly characterized (especially in the context of virus infection), but is a known co-chaperone of heat shock protein 90 (HSP90). HSP90 has a well-characterized pro-viral role during the replication of diverse herpesviruses, and we therefore hypothesized that HSP90 is also pro-viral for BoHV-1. Drug-mediated inhibition of HSP90 using geldanamycin at sub-cytotoxic concentrations inhibited both BoHV-1 protein production and viral genome replication, indicating a pro-viral role for HSP90 during BoHV-1 infection. Our data demonstrates pro-viral roles for both TTC4 and HSP90 during BoHV-1 replication; possibly, interactions between these two proteins are required for optimal BoHV-1 replication, or the two proteins may have independent pro-viral roles.
Keywords	Bovine alphaherpesvirus 1 ; cattle ; heat-shock protein 90 ; infectious bovine rhinotracheitis ; protein synthesis ; research ; viral genome ; virus replication ; viruses
Language	English
Dates of publication	2022-11
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	605780-9
ISSN	1872-7492 ; 0168-1702
ISSN (online)	1872-7492
ISSN	0168-1702
DOI	10.1016/j.virusres.2022.198927
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: CpG dinucleotide enrichment in the influenza A virus genome as a live attenuated vaccine development strategy.

Sharp, Colin P / Thompson, Beth H / Nash, Tessa J / Diebold, Ola / Pinto, Rute M / Thorley, Luke / Lin, Yao-Tang / Sives, Samantha / Wise, Helen / Clohisey Hendry, Sara / Grey, Finn / Vervelde, Lonneke / Simmonds, Peter / Digard, Paul / Gaunt, Eleanor R

PLoS pathogens

2023 Volume 19, Issue 5, Page(s) e1011357

Abstract: Synonymous recoding of RNA virus genomes is a promising approach for generating attenuated viruses to use as vaccines. Problematically, recoding typically hinders virus growth, but this may be rectified using CpG dinucleotide enrichment. CpGs are ... ...

Abstract	Synonymous recoding of RNA virus genomes is a promising approach for generating attenuated viruses to use as vaccines. Problematically, recoding typically hinders virus growth, but this may be rectified using CpG dinucleotide enrichment. CpGs are recognised by cellular zinc-finger antiviral protein (ZAP), and so in principle, removing ZAP sensing from a virus propagation system will reverse attenuation of a CpG-enriched virus, enabling high titre yield of a vaccine virus. We tested this using a vaccine strain of influenza A virus (IAV) engineered for increased CpG content in genome segment 1. Virus attenuation was mediated by the short isoform of ZAP, correlated with the number of CpGs added, and was enacted via turnover of viral transcripts. The CpG-enriched virus was strongly attenuated in mice, yet conveyed protection from a potentially lethal challenge dose of wildtype virus. Importantly for vaccine development, CpG-enriched viruses were genetically stable during serial passage. Unexpectedly, in both MDCK cells and embryonated hens' eggs that are used to propagate live attenuated influenza vaccines, the ZAP-sensitive virus was fully replication competent. Thus, ZAP-sensitive CpG enriched viruses that are defective in human systems can yield high titre in vaccine propagation systems, providing a realistic, economically viable platform to augment existing live attenuated vaccines.
MeSH term(s)	Animals ; Female ; Humans ; Mice ; Influenza A virus/genetics ; Vaccines, Attenuated ; Chickens ; Viral Vaccines/genetics ; Vaccine Development ; Influenza Vaccines ; Virus Replication
Chemical Substances	Vaccines, Attenuated ; Viral Vaccines ; Influenza Vaccines
Language	English
Publishing date	2023-05-05
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.1011357
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Article ; Online: The molecular basis of differential host responses to avian influenza viruses in avian species with differing susceptibility.

Frontiers in cellular and infection microbiology

2023 Volume 13, Page(s) 1067993

Abstract: Introduction: Highly pathogenic avian influenza (HPAI) viruses, such as H5N1, continue to pose a serious threat to animal agriculture, wildlife and to public health. Controlling and mitigating this disease in domestic birds requires a better ... ...

Abstract	Introduction: Highly pathogenic avian influenza (HPAI) viruses, such as H5N1, continue to pose a serious threat to animal agriculture, wildlife and to public health. Controlling and mitigating this disease in domestic birds requires a better understanding of what makes some species highly susceptible (such as turkey and chicken) while others are highly resistant (such as pigeon and goose). Susceptibility to H5N1 varies both with species and strain; for example, species that are tolerant of most H5N1 strains, such as crows and ducks, have shown high mortality to emerging strains in recent years. Therefore, in this study we aimed to examine and compare the response of these six species, to low pathogenic avian influenza (H9N2) and two strains of H5N1 with differing virulence (clade 2.2 and clade 2.3.2.1) to determine how susceptible and tolerant species respond to HPAI challenge. Methods: Birds were challenged in infection trials and samples (brain, ileum and lung) were collected at three time points post infection. The transcriptomic response of birds was examined using a comparative approach, revealing several important discoveries. Results: We found that susceptible birds had high viral loads and strong neuro-inflammatory response in the brain, which may explain the neurological symptoms and high mortality rates exhibited following H5N1 infection. We discovered differential regulation of genes associated with nerve function in the lung and ileum, with stronger differential regulation in resistant species. This has intriguing implications for the transmission of the virus to the central nervous system (CNS) and may also indicate neuro-immune involvement at the mucosal surfaces. Additionally, we identified delayed timing of the immune response in ducks and crows following infection with the more deadly H5N1 strain, which may account for the higher mortality in these species caused by this strain. Lastly, we identified candidate genes with potential roles in susceptibility/resistance which provide excellent targets for future research. Discussion: This study has helped elucidate the responses underlying susceptibility to H5N1 influenza in avian species, which will be critical in developing sustainable strategies for future control of HPAI in domestic poultry.
MeSH term(s)	Animals ; Influenza in Birds ; Influenza A Virus, H5N1 Subtype ; Influenza A Virus, H9N2 Subtype ; Ducks ; Chickens
Language	English
Publishing date	2023-02-28
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2619676-1
ISSN	2235-2988 ; 2235-2988
ISSN (online)	2235-2988
ISSN	2235-2988
DOI	10.3389/fcimb.2023.1067993
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Article ; Online: Exploiting horizontal pleiotropy to search for causal pathways within a Mendelian randomization framework.

Cho, Yoonsu / Haycock, Philip C / Sanderson, Eleanor / Gaunt, Tom R / Zheng, Jie / Morris, Andrew P / Davey Smith, George / Hemani, Gibran

Nature communications

2020 Volume 11, Issue 1, Page(s) 1010

Abstract: In Mendelian randomization (MR) analysis, variants that exert horizontal pleiotropy are typically treated as a nuisance. However, they could be valuable in identifying alternative pathways to the traits under investigation. Here, we develop MR-TRYX, a ... ...

Abstract	In Mendelian randomization (MR) analysis, variants that exert horizontal pleiotropy are typically treated as a nuisance. However, they could be valuable in identifying alternative pathways to the traits under investigation. Here, we develop MR-TRYX, a framework that exploits horizontal pleiotropy to discover putative risk factors for disease. We begin by detecting outliers in a single exposure-outcome MR analysis, hypothesising they are due to horizontal pleiotropy. We search across hundreds of complete GWAS summary datasets to systematically identify other (candidate) traits that associate with the outliers. We develop a multi-trait pleiotropy model of the heterogeneity in the exposure-outcome analysis due to pathways through candidate traits. Through detailed investigation of several causal relationships, many pleiotropic pathways are uncovered with already established causal effects, validating the approach, but also alternative putative causal pathways. Adjustment for pleiotropic pathways reduces the heterogeneity across the analyses.
MeSH term(s)	Causality ; Computer Simulation ; Databases, Genetic ; Disease/genetics ; Genetic Pleiotropy ; Genetic Variation ; Genome-Wide Association Study ; Humans ; Mendelian Randomization Analysis ; Models, Genetic ; Phenotype ; Polymorphism, Single Nucleotide ; Risk Factors
Language	English
Publishing date	2020-02-21
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/s41467-020-14452-4
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Article ; Online: Exploiting horizontal pleiotropy to search for causal pathways within a Mendelian randomization framework

Yoonsu Cho / Philip C. Haycock / Eleanor Sanderson / Tom R. Gaunt / Jie Zheng / Andrew P. Morris / George Davey Smith / Gibran Hemani

Nature Communications, Vol 11, Iss 1, Pp 1-

2020 Volume 13

Abstract: In Mendelian randomization (MR) studies, one typically selects SNPs as instrumental variables that do not directly affect the outcome to avoid violation of MR assumptions. Here, Cho et al. present a framework, MR-TRYX, that leverages knowledge of such ... ...

Abstract	In Mendelian randomization (MR) studies, one typically selects SNPs as instrumental variables that do not directly affect the outcome to avoid violation of MR assumptions. Here, Cho et al. present a framework, MR-TRYX, that leverages knowledge of such outliers of horizontal pleiotropy to identify putative causal relationships between exposure and outcome.
Keywords	Science ; Q
Language	English
Publishing date	2020-02-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Exploiting horizontal pleiotropy to search for causal pathways within a Mendelian randomization framework

Yoonsu Cho / Philip C. Haycock / Eleanor Sanderson / Tom R. Gaunt / Jie Zheng / Andrew P. Morris / George Davey Smith / Gibran Hemani

Nature Communications, Vol 11, Iss 1, Pp 1-

2020 Volume 13

Abstract	In Mendelian randomization (MR) studies, one typically selects SNPs as instrumental variables that do not directly affect the outcome to avoid violation of MR assumptions. Here, Cho et al. present a framework, MR-TRYX, that leverages knowledge of such outliers of horizontal pleiotropy to identify putative causal relationships between exposure and outcome.
Keywords	Science ; Q
Language	English
Publishing date	2020-02-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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