Ontology highlight
ABSTRACT:
PROVIDER: PRJNA727012 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14408733_1.fastq.gz | Fastqsanger.gz | |||
| SRR14408733_2.fastq.gz | Fastqsanger.gz | |||
| SRR14408734_1.fastq.gz | Fastqsanger.gz | |||
| SRR14408734_2.fastq.gz | Fastqsanger.gz | |||
| SRR14408735_1.fastq.gz | Fastqsanger.gz |
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Project description:Single cell RNA sequencing analysis was performed on bronchoalveolar lavage samples obtained from Rhesus macaques on day 2 after intranasal/intratracheal infection with SARS-CoV-2 B.1.351/beta variant 4 weeks after the second dose of 30ug mRNA-1273 vaccine along with unvaccinated controls
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Project description:Emergence of SARS-CoV-2 variants of concern (VOCs), including the globally successful Alpha (B.1.1.7) variant, suggests viral adaptation to enhance human-to-human transmission. Although much effort has focused on characterisation of spike changes, Alpha mutations outside spike likely contribute to adaptation. Here we used RNAseq as well as viral replication assays to show that Alpha isolates more effectively suppress innate immune responses (ISGs as assessed by RNA) in airway epithelial cells, compared to first wave isolates. We found that Alpha has dramatically increased subgenomic RNA and protein levels of N, Orf9b and Orf6, all known innate immune antagonists.
2021-12-31 | E-MTAB-11275 | biostudies-arrayexpress
Project description:The Covid-19 pandemic is exacting an increasing toll worldwide, with new SARS-CoV-2 variants emerging that exhibit higher infectivity rates and which may partially evade vaccine and antibody immunity. Rapid deployment of non-invasive therapeutic avenues capable of preventing infection by all SARS-CoV-2 variants could complement current vaccination efforts and help turn the tide on the Covid-19 pandemic. Here, we describe a novel therapeutic strategy targeting the SARS-CoV-2 RNA using locked nucleic acid antisense oligonucleotides (LNA ASOs). We identified an LNA ASO binding to the 5’ leader sequence of SARS-CoV-2 ORF1a/b and which disrupts a highly conserved stem-loop structure, with nanomolar efficacy in preventing viral replication in human cells. Daily intranasal administration of this LNA ASO in the K18-hACE2 humanized Covid-19 mouse model potently (98-99%) suppressed viral replication in the lungs of infected mice, revealing strong prophylactic and treatment effects. We found that the LNA ASO is highly efficacious in countering all SARS-CoV-2 variants of concern (VOC) tested in vitro and in vivo, including B.1.427 (CA), B.1.1.7 (UK), and B.1.351 (SA) variants. LNA ASOs are chemically stable and can be flexibly modified to target different viral RNA sequences. Hence, virus-targeting LNA ASOs represent a promising therapeutic approach to reduce the transmission of SARS-CoV-2, especially in areas where vaccine distribution is a challenge, and it may be stockpiled for future coronavirus pandemics.
2022-06-30 | GSE174382 | GEO
Project description:The ancestral SARS-CoV-2 strain that initiated the Covid-19 pandemic at the end of 2019 has rapidly mutated into multiple variants of concern with variable pathogenicity and increasing immune escape strategies. However, differences in host cellular antiviral responses upon infection with SARS-CoV-2 variants remains elusive. Leveraging whole cell proteomics, we determined host signalling pathways that are differentially modulated upon infection with the clinical isolates of the ancestral SARS-CoV-2 B.1 and the variants of concern Delta and Omicron BA.1. Our findings illustrate alterations in the global host proteome landscape upon infection with SARS-CoV-2 variants and the resulting host immune responses. Additionally, viral proteome kinetics reveal declining levels of viral protein expression during Omicron BA.1 infection when compared to ancestral B.1 and Delta variants, consistent with its reduced replication rates. Moreover, molecular assays reveal deferral activation of specific host antiviral signalling upon Omicron BA.1 and BA.2 infection. Our study provides an overview of host proteome profile of multiple SARS-CoV-2 variants and brings forth a better understanding of the instigation of key immune signalling pathways causative for the differential pathogenicity of SARS-CoV-2 variants.
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Project description:SARS-CoV-2 lineage B.1.1.7 viruses are more transmissible, may lead to greater clinical severity, and result in modest reductions in antibody neutralization. Subgenomic RNA(sgRNA) is produced by discontinuous transcription of the SARS-CoV-2 genome. Applying our tool(periscope) to ARTIC Network Nanopore genomic sequencing data from 4400 SARS-CoV-2 positive clinical samples, we show that normalised sgRNA is significantly increased in B.1.1.7(alpha) infections(n=879). This increase is seen over the previous dominant circulating UK lineage, B.1.177(n=943), which is independent of genomic reads, E-gene cycle-threshold and days since symptom onset at sampling. A noncanonical sgRNA which could represent ORF9b is found in 98.4% of B.1.1.7 SARS-CoV-2 infections compared with only 13.8% of other lineages, with a 16-fold increase in median sgRNA abundance. We demonstrate that ORF9b protein levels are increased 6-fold in B.1.1.7 compared to a B lineage virus during in vitro culture. We hypothesise that this enhanced presence of ORF9b in B.1.1.7 viruses is a direct consequence of a triple nucleotide mutation in nucleocapsid(28280:GAT>CAT,D3L) creating a transcription regulatory-like sequence complementary to a region 3’ of the genomic leader. These findings provide a unique insight into the biology of B.1.1.7 and support monitoring of sgRNA profiles in sequence data to evaluate emerging potential variants of concern.
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Project description:Enhanced fitness of SARS-CoV-2 variant of concern B.1.1.7, but not B.1.351, in animal models
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Project description:The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has had devastating impacts on our global society. Although vaccines and monoclonal antibody countermeasures have reduced the morbidity and mortality associated with SARS-CoV-2 infection, variants with constellations of mutations in the spike gene threaten their efficacy. Therefore, antiviral interventions that are resistant to further virus evolution may be needed. Here, we show IFN-λ protects against SARS-CoV-2 B.1.351 (Beta) and B.1.1529 (Omicron) variants in three strains of conventional and human ACE2 transgenic mice. Prophylaxis or therapy with nasally-delivered IFN-λ2 limited infection of historical or variant (B.1.351 and B.1.1.529) SARS-CoV-2 strains in both the upper and lower respiratory tracts without causing excessive inflammation. In the lung, IFN-λ was produced preferentially in epithelial cells and acted on radio-resistant cells to protect against of SARS-CoV-2 infection. Thus, inhaled IFN-λ may have promise as a treatment for evolving SARS-CoV-2 variants that develop resistance to antibody-based countermeasures.
2022-02-08 | GSE193990 | GEO
Project description:Since the start of the coronavirus disease-2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused more than 2 million deaths worldwide. Many vaccines have been deployed to date; however, the continual evolution of the viral receptor binding domain (RBD) has recently challenged their efficacy. In particular, SARS-CoV-2 variants originating in South Africa (B.1.351) and the U.K. (B.1.1.7) have reduced plasma neutralization activity and crippled antibody cocktails that received emergency use authorization1-3. Whereas vaccines can be updated periodically to account for emerging variants, complementary strategies are urgently needed to overcome viral escape. One potential alternative are camelid VHHs (also known as nanobodies), which can access conserved epitopes often hidden to conventional antibodies4-6. We here isolate anti-RBD nanobodies from llamas and mice engineered to produce VHHs from alpacas, dromedaries and camels. Through neutralization assays and cryo-electron microscopy we identify two “nanomouse” VHHs that circumvent RBD antigenic drift by recognizing a domain conserved in coronaviruses, away from the ACE2 binding motif. Conversely, llama nanobodies recognize the RBD-ACE2 interphase and as monomers they are ineffective against E484K or N501Y substitutions. Notably, as homotrimers those same VHHs neutralize RBD variants with ultrahigh (pM) affinity, rivaling the most potent antibodies produced to date against SARS-CoV-2. We conclude that multivalent nanobodies can avert SARS-CoV-2 escape mutants and thus they represent promising tools to prevent COVID-19 mortality when vaccines are compromised.
2021-05-18 | GSE167310 | GEO
Project description:Despite the clinical success of anti-spike vaccines, the effectiveness of neutralizing antibodies and vaccines by rapidly spreading SARS-CoV-2 variants has been compromised. Viruses can hijack the glycosylation machinery of host cells to shield themselves from the host’s immune response and attenuate antibody efficiency. However, it still remains unclear whether targeting glycosylation on spike can impair SARS-CoV-2 and its variants infectivity. Methods: To assess the binding ability of glycosylated or deglycosylated spike with ACE2, we performed flow cytometry, ELISA, and BioLayer Interferometry methods. Viral entry ability was determined by luciferase intensity, immunoblotting, and immunofluorescence assay. A genome-wide association study (GWAS) was performed to identify the relationship of STT3A and COVID-19 severity. N-glycosylation regulated by NF-kB/STT3A axis was investigated by knockdown approach, chromatin immunoprecipitation, and promoter assay. To specifically target SARS-CoV-2 infected cells, we developed an antibody-drug conjugate coupling non-neutralization anti-spike antibody with NGI-1 (4G10-ADC) on inhibitory effects of SARS-CoV-2 infection. Results: We found receptor binding domain and three SARS-CoV-2 distinct surface Nglycosylation sites in 57,311 spikes retrieved from NCBI-Virus-database are highly evolutionarily conserved (99.67%) and involved in ACE2 interaction. We further identified STT3A as a key glycosyltransferase that catalyzed spike glycosylation and positively correlated with COVID-19 severity. Inhibition of STT3A by N-linked glycosylation inhibitor-1 (NGI-1) impaired SARS-CoV-2 and its variants (B.1.1.7, and B.1.351) infectivity. Most importantly, 4G10-ADC internalized SARS-CoV-2 infected cells and subsequently released NGI-1 to deglycosylate spike protein. Thereby, it reinforces the neutralizing abilities in antibodies, vaccines, or convalescent sera, inhibiting SARS-CoV-2 and its variants’ infectivity. Our results suggest targeting STT3A-mediated evolution conserved glycosylation via ADC can provide a widespread impact on SARS-CoV-2 variants infection. Together, we identified a novel deglycosylation method to eradicate SARS-CoV-2 variants infection.
2021-07-30 | PXD026852 | Pride
Project description:Single cell RNA sequencing analysis was performed on bronchoalveolar lavage samples obtained from Rhesus macaques infected intranasally/intratracheally with SARS-CoV-2 after vaccination with mRNA-1273 vaccine
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