Ontology highlight
ABSTRACT:
PROVIDER: PRJNA726840 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14460618_1.fastq.gz | Fastqsanger.gz | |||
| SRR14460618_2.fastq.gz | Fastqsanger.gz | |||
| SRR14460619_1.fastq.gz | Fastqsanger.gz | |||
| SRR14460619_2.fastq.gz | Fastqsanger.gz | |||
| SRR14460620_1.fastq.gz | Fastqsanger.gz |
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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 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: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:hACE2 transgenic mice were infected with the original SARS-CoV-2 strain (B.1) and the Beta (B.1.351) variant. Lung and spleen samples were collected 1 day post infection (DPI), 3 DPI and 5 DPI, and mRNA was sequenced.
2023-09-22 | E-MTAB-13308 | biostudies-arrayexpress
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: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:A new phase of the COVID-19 pandemic has started as SARS-CoV-2 variants with increased transmissibility are emerging globally, calling for the development of reliable platforms to rapidly phenotype viruses. Currently, no rapid phenotyping system exists that both accurately models human biology and can be standardized properly. Organoids accurately model viral target cells in vivo, can be established from many tissues, passaged indefinitely, biobanked and shared. We found that the British variant (clade B.1.1.7), compared to an ancestral 614G-containing clade B virus, produced higher levels of infectious virus late in infection and had a higher replicative fitness in human airway, alveolar and intestinal organoid models. Our findings unveil extended shedding as a correlate of fitness for SARS-CoV-2, possibly explaining the rapid emergence of SARS-CoV-2 B.1.1.7. Combined with genomic surveillance systems, virus phenotyping using standardized organoid models may be implemented into public health decision making.
2024-06-13 | GSE178333 | GEO
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.
2021-11-26 | PXD029954 | Pride
Project description:The COVID-19 pandemic prompted an unprecedented effort to develop effective countermeasures against SARS-CoV-2. While efficacious vaccines and certain therapeutic monoclonal antibodies are available, here, we report the development, cryo-EM structures and functional analyses of distinct potent monoclonal antibodies (mAbs) that neutralize SARS-CoV-2 and its variant B.1.351. We established a platform for rapid identification of highly potent and specific SARS-CoV-2-neutralizing antibodies by high-throughput B cell receptor single cell sequencing of spike receptor binding domain immunized animals. We identified two highly potent and specific SARS-CoV-2 neutralizing mAb clones that have single-digit nanomolar affinity and low-picomolar avidity. We also generated a bispecific antibody of these two lead clones. The lead monospecific and bispecific antibodies showed strong neutralization ability against prototypical SARS-CoV-2 and the highly contagious South African variant B.1.351 that post a further risk of reducing the efficacy of currently available therapeutic antibodies and vaccines. The lead mAbs showed potent in vivo efficacy against authentic SARS-CoV-2 in both prophylactic and therapeutic settings. We solved five cryo-EM structures at ~3 resolution of these neutralizing antibodies in complex with the ectodomain of the prefusion spike trimer, and revealed the molecular epitopes, binding patterns and conformations between the antibodies and spike RBD, which are distinct from existing antibodies. Our recently developed antibodies expand the repertoire of the toolbox of COVID-19 countermeasures against the SARS-CoV-2 pathogen and its emerging variants.
2022-01-11 | GSE174635 | GEO
Project description:The SARS-CoV-2 virus is continuously evolving, with appearance of new variants characterized by multiple genomic mutations, some of which can affect functional properties, including infectivity, interactions with host immunity, and disease severity. The rapid spread of new SARS-CoV-2 variants has highlighted the urgency to trace the virus evolution, to help limit its diffusion, and to assess effectiveness of containment strategies. We propose here a PCR-based rapid, sensitive and low-cost allelic discrimination assay panel for the identification of SARS-CoV-2 genotypes, useful for detection in different sample types, such as nasopharyngeal swabs and wastewater. The tests carried out demonstrate that this in-house assay, whose results were confirmed by SARS-CoV-2 whole-genome sequencing, can detect variations in up to 10 viral genome positions at once and is specific and highly sensitive for identification of all tested SARS-CoV-2 clades, even in the case of samples very diluted and of poor quality, particularly difficult to analyze.
2022-06-03 | E-MTAB-11261 | biostudies-arrayexpress