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Article ; Online: Immune interaction between SARS-CoV-2 and

Booysen, Petro / Wilkinson, Katalin A / Sheerin, Dylan / Waters, Robyn / Coussens, Anna K / Wilkinson, Robert J

2023 Volume 14, Page(s) 1254206

Abstract: SARS-CoV-2 ... ...

Abstract	SARS-CoV-2 and
MeSH term(s)	Humans ; Animals ; Mice ; Mycobacterium tuberculosis ; SARS-CoV-2 ; COVID-19 ; Coinfection ; Tuberculosis/prevention & control
Language	English
Publishing date	2023-09-27
Publishing country	Switzerland
Document type	Journal Article ; Review ; 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.2023.1254206
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Inclusion of a dual signal sequence enhances the immunogenicity of a novel viral vectored vaccine against the capsular group B meningococcus.

Sheerin, Dylan / Dold, Christina / Silva-Reyes, Laura / Linder, Aline / Pollard, Andrew J / Rollier, Christine S

Cell & bioscience

2022 Volume 12, Issue 1, Page(s) 86

Abstract: Background: Disease caused by the capsular group B meningococcus (MenB) is the leading cause of infectious death in UK infants. A novel adenovirus-based vaccine encoding the MenB factor H binding protein (fHbp) with an N-terminal dual signal sequence ... ...

Abstract	Background: Disease caused by the capsular group B meningococcus (MenB) is the leading cause of infectious death in UK infants. A novel adenovirus-based vaccine encoding the MenB factor H binding protein (fHbp) with an N-terminal dual signal sequence induces high titres of protective antibody after a single dose in mice. A panel of N-terminal signal sequence variants were created to assess the contribution of components of this sequence to transgene expression kinetics of the encoded antigen from mammalian cells and the resultant effect on immunogenicity of fHbp. Results: The full-length signal sequence (FL SS) resulted in superior early antigen expression compared with the panel of variants, as measured by flow cytometry and confocal imaging, and supported higher bactericidal antibody levels against the expressed antigen in mouse sera < 6 weeks post-immunisation than the licensed four component MenB vaccine. The FL SS also significantly increased antigen-specific T cell responses against other adenovirus-encoded bacterial antigens in mice. Conclusions: These findings demonstrate that the FL SS enhances immunogenicity of the encoded antigen, supporting its inclusion in other viral vectored bacterial antigen transgenes.
Language	English
Publishing date	2022-06-11
Publishing country	England
Document type	Journal Article
ZDB-ID	2593367-X
ISSN	2045-3701
ISSN	2045-3701
DOI	10.1186/s13578-022-00809-3
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Necroptosis does not drive disease pathogenesis in a mouse infective model of SARS-CoV-2 in vivo.

M Bader, Stefanie / Cooney, James P / Bhandari, Reet / Mackiewicz, Liana / Dayton, Merle / Sheerin, Dylan / Georgy, Smitha Rose / Murphy, James M / Davidson, Kathryn C / Allison, Cody C / Pellegrini, Marc / Doerflinger, Marcel

Cell death & disease

2024 Volume 15, Issue 1, Page(s) 100

Abstract: Necroptosis, a type of lytic cell death executed by the pseudokinase Mixed Lineage Kinase Domain-Like (MLKL) has been implicated in the detrimental inflammation caused by SARS-CoV-2 infection. We minimally and extensively passaged a single clinical SARS- ... ...

Abstract	Necroptosis, a type of lytic cell death executed by the pseudokinase Mixed Lineage Kinase Domain-Like (MLKL) has been implicated in the detrimental inflammation caused by SARS-CoV-2 infection. We minimally and extensively passaged a single clinical SARS-CoV-2 isolate to create models of mild and severe disease in mice allowing us to dissect the role of necroptosis in SARS-CoV-2 disease pathogenesis. We infected wild-type and MLKL-deficient mice and found no significant differences in viral loads or lung pathology. In our model of severe COVID-19, MLKL-deficiency did not alter the host response, ameliorate weight loss, diminish systemic pro-inflammatory cytokines levels, or prevent lethality in aged animals. Our in vivo models indicate that necroptosis is dispensable in the pathogenesis of mild and severe COVID-19.
MeSH term(s)	Animals ; Mice ; SARS-CoV-2/metabolism ; Necroptosis/physiology ; Protein Kinases/metabolism ; COVID-19 ; Disease Models, Animal ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism
Chemical Substances	Protein Kinases (EC 2.7.-) ; Receptor-Interacting Protein Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2024-01-30
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2541626-1
ISSN	2041-4889 ; 2041-4889
ISSN (online)	2041-4889
ISSN	2041-4889
DOI	10.1038/s41419-024-06471-6
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Article ; Online: Identification and control for the effects of bioinformatic globin depletion on human RNA-seq differential expression analysis.

Sheerin, Dylan / Lakay, Francisco / Esmail, Hanif / Kinnear, Craig / Sansom, Bianca / Glanzmann, Brigitte / Wilkinson, Robert J / Ritchie, Matthew E / Coussens, Anna K

Scientific reports

2023 Volume 13, Issue 1, Page(s) 1859

Abstract: When profiling blood samples by RNA-sequencing (RNA-seq), RNA from haemoglobin (Hgb) can account for up to 70% of the transcriptome. Due to considerations of sequencing depth and power to detect biological variation, Hgb RNA is typically depleted prior ... ...

Abstract	When profiling blood samples by RNA-sequencing (RNA-seq), RNA from haemoglobin (Hgb) can account for up to 70% of the transcriptome. Due to considerations of sequencing depth and power to detect biological variation, Hgb RNA is typically depleted prior to sequencing by hybridisation-based methods; an alternative approach is to deplete reads arising from Hgb RNA bioinformatically. In the present study, we compared the impact of these two approaches on the outcome of differential gene expression analysis performed using RNA-seq data from 58 human tuberculosis (TB) patient or contact whole blood samples-29 globin kit-depleted and 29 matched non-depleted-a subset of which were taken at TB diagnosis and at six months post-TB treatment from the same patient. Bioinformatic depletion of Hgb genes from the non-depleted samples (bioinformatic-depleted) substantially reduced library sizes (median = 57.24%) and fewer long non-coding, micro, small nuclear and small nucleolar RNAs were captured in these libraries. Profiling published TB gene signatures across all samples revealed inferior correlation between kit-depleted and bioinformatic-depleted pairs when the proportion of reads mapping to Hgb genes was higher in the non-depleted sample, particularly at the TB diagnosis time point. A set of putative "globin-fingerprint" genes were identified by directly comparing kit-depleted and bioinformatic-depleted samples at each timepoint. Two TB treatment response signatures were also shown to have decreased differential performance when comparing samples at TB diagnosis to six months post-TB treatment when profiled on the bioinformatic-depleted samples compared with their kit-depleted counterparts. These results demonstrate that failure to deplete Hgb RNA prior to sequencing has a negative impact on the sensitivity to detect disease-relevant gene expression changes even when bioinformatic removal is performed.
MeSH term(s)	Humans ; Gene Expression Profiling/methods ; Hemoglobins/genetics ; RNA/genetics ; RNA, Messenger/genetics ; RNA-Seq ; Sequence Analysis, RNA ; Transcriptome ; Computational Biology
Chemical Substances	Hemoglobins ; RNA (63231-63-0) ; RNA, Messenger
Language	English
Publishing date	2023-02-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-28218-7
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Article ; Online: Distinct and overlapping immunological responses to SARS-CoV-2 and Mycobacterium tuberculosis identified by single-cell RNA-seq of co-infected whole blood

Sheerin, Dylan / Phan, Thanh Kha / Eriksson, Emily M. / COVID PROFILE Consortium / Coussens, Anna K

medRxiv

Abstract: Introduction: COVID-19 and tuberculosis (TB) exhibit similar symptomatic presentation and clinical parameters. Common underlying immunological mechanisms also highlight potential routes of immunopathogenic interaction between these diseases during co- ... ...

Abstract	Introduction: COVID-19 and tuberculosis (TB) exhibit similar symptomatic presentation and clinical parameters. Common underlying immunological mechanisms also highlight potential routes of immunopathogenic interaction between these diseases during co-infection. To explore immunological similarities, differences and interactions, single-cell RNA-seq (scRNA-seq) was performed on whole blood infected with Mycobacterium tuberculosis (Mtb), SARS-CoV-2, or both pathogens. Methods: Whole blood from four healthy adults, were subjected to ex vivo infection with Mtb and/or SARS-CoV-2 ancestral strain, or were maintained in an uninfected state, for 24 or 96 hours. At each timepoint, for each condition, the four biological replicates were captured, fixed and cryopreserved to be processed for scRNA-seq as a single batch. Following quality control filtering, genotype-based demultiplexing was performed to obtain data from each biological replicate for pseudobulk differential expression analysis. Results: Thirteen distinct clusters of cells were identified based on marker gene expression. Profound differences in the proportions of monocytes, T cells and neutrophils were observed between infection conditions and timepoints. The greatest divergence between pathogen responses occurred within myeloid cells at early timepoints of infection. Co-infection had the greatest synergistic effect 24 hours post-infection with 238 immunological pathways uniquely enriched, including IFN-γ and TNF production, whilst by 96 hours post-infection there was a large overlap of 182 shared pathways between Mtb, SARS-CoV-2 and co-infection. SARS-CoV-2-only infection resulted in widespread cell death by 96 hours post-infection, while Mtb-only and co-infected samples remained enriched for monocyte, T cell and NK cell signatures, sharing negative regulation of extrinsic apoptotic signalling. Distinct from Mtb, SARS-Co-V-2 had unique regulating of αβ T cell activation and differentiation at both time points. Conclusion: These data provide a high-resolution characterisation of distinct and overlapping immunological responses generated by SARS-CoV-2 and Mtb when a single infection or co-infection occurs. This sheds light on the potential effects of novel or existing host-directed therapies that target these pathways, which is particularly crucial for settings where dual presentation is common.
Keywords	covid19
Language	English
Publishing date	2023-05-29
Publisher	Cold Spring Harbor Laboratory Press
Document type	Article ; Online
DOI	10.1101/2023.05.24.23290499
Database	COVID19

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Article: Systematic evaluation of transcriptomic disease risk and diagnostic biomarker overlap between COVID-19 and tuberculosis: a patient-level meta-analysis.

Sheerin, Dylan / Abhimanyu / Wang, Xutao / Johnson, W Evan / Coussens, Anna

medRxiv : the preprint server for health sciences

2020

Abstract: Background: The novel coronavirus, SARS-CoV-2, has increased the burden on healthcare systems already strained by a high incidence of tuberculosis (TB) as co-infection and dual presentation are occurring in syndemic settings. We aimed to understand the ... ...

Abstract	Background: The novel coronavirus, SARS-CoV-2, has increased the burden on healthcare systems already strained by a high incidence of tuberculosis (TB) as co-infection and dual presentation are occurring in syndemic settings. We aimed to understand the interaction between these diseases by profiling COVID-19 gene expression signatures on RNA-sequencing data from TB-infected individuals. Methods: We performed a systematic review and patient-level meta-analysis by querying PubMed and pre-print servers to derive eligible COVID-19 gene expression signatures from human whole blood (WB), PBMCs or BALF studies. A WB influenza dataset served as a control respiratory disease signature. Three large TB RNA-seq datasets, comprising multiple cohorts from the UK and Africa and consisting of TB patients across the disease spectrum, were chosen to profile these signatures. Putative "COVID-19 risk scores" were generated for each sample in the TB datasets using the TBSignatureProfiler package. Risk was stratified by time to TB diagnosis in progressors and contacts of pulmonary and extra-pulmonary TB. An integrative analysis between TB and COVID-19 single-cell RNA-seq data was performed and a population-level meta-analysis was conducted to identify shared gene ontologies between the diseases and their relative enrichment in COVID-19 disease severity states. Results: 35 COVID-19 gene signatures from nine eligible studies comprising 98 samples were profiled on TB RNA-seq data from 1181 samples from 853 individuals. 25 signatures had significantly higher COVID-19 risk in active TB (ATB) compared with latent TB infection (p <0·005), 13 of which were validated in two independent datasets. Interpretation: Our results identify shared dysregulation of immune responses in COVID-19 and TB as a dual risk posed by co-infection to COVID-19 severity and TB disease progression. These individuals should be followed up for TB in the months subsequent to SARS-CoV-2 diagnosis.
Language	English
Publishing date	2020-11-26
Publishing country	United States
Document type	Preprint
DOI	10.1101/2020.11.25.20236646
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Article ; Online: Immunopathogenic overlap between COVID-19 and tuberculosis identified from transcriptomic meta-analysis and human macrophage infection.

Sheerin, Dylan / Abhimanyu / Peton, Nashied / Vo, William / Allison, Cody Charles / Wang, Xutao / Johnson, W Evan / Coussens, Anna Kathleen

iScience

2022 Volume 25, Issue 6, Page(s) 104464

Abstract: Current and previous tuberculosis (TB) increase the risk of COVID-19 mortality and severe disease. To identify mechanisms of immunopathogenic interaction between COVID-19 and TB, we performed a systematic review and patient-level meta-analysis of COVID- ... ...

Abstract	Current and previous tuberculosis (TB) increase the risk of COVID-19 mortality and severe disease. To identify mechanisms of immunopathogenic interaction between COVID-19 and TB, we performed a systematic review and patient-level meta-analysis of COVID-19 transcriptomic signatures, spanning disease severity, from whole blood, PBMCs, and BALF. 35 eligible signatures were profiled on 1181 RNA-seq samples from 853 individuals across the spectrum of TB infection. Thirteen COVID-19 gene-signatures had significantly higher "COVID-19 risk scores" in active TB and latent TB progressors compared with non-progressors and uninfected controls (p<0·005), in three independent cohorts. Integrative single-cell-RNAseq analysis identified
Language	English
Publishing date	2022-05-25
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2022.104464
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Article ; Online: Distinct patterns of whole blood transcriptional responses are induced in mice following immunisation with adenoviral and poxviral vector vaccines encoding the same antigen.

Sheerin, Dylan / Dold, Christina / O'Connor, Daniel / Pollard, Andrew J / Rollier, Christine S

BMC genomics

2021 Volume 22, Issue 1, Page(s) 777

Abstract: Background: Viral vectors, including adenovirus (Ad) and modified vaccinia Ankara (MVA), have gained increasing attention as vaccine platforms in recent years due to their capacity to express antigens from a wide array of pathogens, their rapid ... ...

Abstract	Background: Viral vectors, including adenovirus (Ad) and modified vaccinia Ankara (MVA), have gained increasing attention as vaccine platforms in recent years due to their capacity to express antigens from a wide array of pathogens, their rapid induction of humoral and cellular protective immune responses, and their relatively low production costs. In particular, the chimpanzee Ad vector, ChAdOx1, has taken centre stage as a leading COVID-19 vaccine candidate. However, despite mounting data, both clinical and pre-clinical, demonstrating effective induction of adaptive immune responses, the innate immune signals that precede the protective responses that make these vectors attractive vaccine platforms remain poorly understood. Results: In this study, a mouse immunisation model was used to evaluate whole blood gene expression changes 24 h after either a single dose or heterologous prime-boost regimen of an Ad and/or MVA vaccine. We demonstrate through comparative analysis of Ad vectors encoding different antigens that a transgene product-specific gene signature can be discerned from the vector-induced transcriptional response. Expression of genes involved in TLR2 stimulation and γδ T cell and natural killer cell activation were induced after a single dose of Ad, while MVA led to greater expression of type I interferon genes. The order of prime-boost combinations was found to influence the magnitude of the gene expression changes, with MVA/Ad eliciting greater transcriptional perturbation than Ad/MVA. Contrasting the two regimens revealed significant enrichment of epigenetic regulation pathways and augmented expression of MHC class I and II molecules associated with MVA/Ad. Conclusion: These data demonstrate that the order in which vaccines from heterologous prime-boost regimens are administered leads to distinct transcriptional responses and may shape the immune response induced by such combinations. The characterisation of early vaccine-induce responses strengthens our understanding of viral vector vaccine mechanisms of action ahead of their characterisation in human clinical trials and are a valuable resource to inform the pre-clinical design of appropriate vaccine constructs for emerging infectious diseases.
MeSH term(s)	Adenoviridae/genetics ; Animals ; COVID-19 ; COVID-19 Vaccines ; Epigenesis, Genetic ; Genetic Vectors/genetics ; Humans ; Immunization ; Mice ; SARS-CoV-2 ; Viral Vaccines
Chemical Substances	COVID-19 Vaccines ; Viral Vaccines
Language	English
Publishing date	2021-10-30
Publishing country	England
Document type	Journal Article
ZDB-ID	2041499-7
ISSN	1471-2164 ; 1471-2164
ISSN (online)	1471-2164
ISSN	1471-2164
DOI	10.1186/s12864-021-08061-8
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Article ; Online: Inclusion of a dual signal sequence enhances the immunogenicity of a novel viral vectored vaccine against the capsular group B meningococcus

Dylan Sheerin / Christina Dold / Laura Silva-Reyes / Aline Linder / Andrew J. Pollard / Christine S. Rollier

Cell & Bioscience, Vol 12, Iss 1, Pp 1-

2022 Volume 15

Abstract: Abstract Background Disease caused by the capsular group B meningococcus (MenB) is the leading cause of infectious death in UK infants. A novel adenovirus-based vaccine encoding the MenB factor H binding protein (fHbp) with an N-terminal dual signal ... ...

Abstract	Abstract Background Disease caused by the capsular group B meningococcus (MenB) is the leading cause of infectious death in UK infants. A novel adenovirus-based vaccine encoding the MenB factor H binding protein (fHbp) with an N-terminal dual signal sequence induces high titres of protective antibody after a single dose in mice. A panel of N-terminal signal sequence variants were created to assess the contribution of components of this sequence to transgene expression kinetics of the encoded antigen from mammalian cells and the resultant effect on immunogenicity of fHbp. Results The full-length signal sequence (FL SS) resulted in superior early antigen expression compared with the panel of variants, as measured by flow cytometry and confocal imaging, and supported higher bactericidal antibody levels against the expressed antigen in mouse sera < 6 weeks post-immunisation than the licensed four component MenB vaccine. The FL SS also significantly increased antigen-specific T cell responses against other adenovirus-encoded bacterial antigens in mice. Conclusions These findings demonstrate that the FL SS enhances immunogenicity of the encoded antigen, supporting its inclusion in other viral vectored bacterial antigen transgenes.
Keywords	Meningococcal disease ; Viral vector vaccines ; Signal sequence ; Transgene ; Expression kinetics ; Biotechnology ; TP248.13-248.65 ; Biology (General) ; QH301-705.5 ; Biochemistry ; QD415-436
Subject code	570
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Immunopathogenic overlap between COVID-19 and tuberculosis identified from transcriptomic meta-analysis and human macrophage infection

Dylan Sheerin / Abhimanyu / Nashied Peton / William Vo / Cody Charles Allison / Xutao Wang / W. Evan Johnson / Anna Kathleen Coussens

iScience, Vol 25, Iss 6, Pp 104464- (2022)

2022

Abstract: Summary: Current and previous tuberculosis (TB) increase the risk of COVID-19 mortality and severe disease. To identify mechanisms of immunopathogenic interaction between COVID-19 and TB, we performed a systematic review and patient-level meta-analysis ... ...

Abstract	Summary: Current and previous tuberculosis (TB) increase the risk of COVID-19 mortality and severe disease. To identify mechanisms of immunopathogenic interaction between COVID-19 and TB, we performed a systematic review and patient-level meta-analysis of COVID-19 transcriptomic signatures, spanning disease severity, from whole blood, PBMCs, and BALF. 35 eligible signatures were profiled on 1181 RNA-seq samples from 853 individuals across the spectrum of TB infection. Thirteen COVID-19 gene-signatures had significantly higher “COVID-19 risk scores” in active TB and latent TB progressors compared with non-progressors and uninfected controls (p<0·005), in three independent cohorts. Integrative single-cell-RNAseq analysis identified FCN1- and SPP1-expressing macrophages enriched in severe COVID-19 BALF and active TB blood. Gene ontology and protein-protein interaction networks identified 12-gene disease-exacerbation hot spots between COVID-19 and TB. Finally, we in vitro validated that SARS-CoV-2 infection is increased in human macrophages cultured in the inflammatory milieu of Mtb-infected macrophages, correlating with TMPRSS2, IFNA1, IFNB1, IFNG, TNF, and IL1B induction.
Keywords	Pathophysiology ; Immunology ; Virology ; Transcriptomics ; Science ; Q
Subject code	610
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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