Effects of Ancestral SARS-CoV-2 versus Variants of Concern Delta and Omicron on Megakaryocyte Activation and Transcriptome
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PROVIDER: PRJNA1162859 | ENA |
REPOSITORIES: ENA
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Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with a hyperreactive platelet phenotype, which is thought to contribute to the high incidence of thrombosis in COVID-19 patients. Mutations of SARS-CoV-2 resulted in several virus variants with differences in transmissibility, infectivity and mortality. This study was designed to investigate how SARS-CoV-2 variants of concern, delta and omicron, affect the transcriptome and function of megakaryocytes (MKs) relative to the ancestral WA1 strain.
2025-08-20 | GSE277576 | GEO
Project description:Ancestral SARS coronavirus-2 (SARS-CoV-2) and variants of concern (VOC) caused a global pandemic with a spectrum of disease variation linked to immune dysfunction. The mechanistic underpinnings of variation related to lung epithelium are relatively understudied. Here, we biobanked lung organoids by preserving stem cell function. We optimized viral infection with H1N1 swine flu and next comprehensively characterized epithelial responses to SARS-CoV-2 infection in phenotypically stable lung organoids from twenty different subjects. We discovered Tetraspanin 8 (TSPAN8) as a novel mediator of SARS-CoV-2-infection. TSPAN8 facilitates SARS-CoV-2 infection rates but does not via enhanced ACE-2-mediated entry. In head-to-head comparisons with Ancestral SARS-CoV-2, Delta- and Omicron- VOC displayed lower overall infection rates of organoids but triggered increased epithelial interferon responses. All variants shared highest tropism for ciliated- and goblet- cells. ACE2- and TSPAN8- expression are universal features of infected cells. TSPAN8-blocking antibodies diminish SARS-CoV-2 infection and may spur novel avenues for COVID-19 therapy.
2022-09-30 | GSE211562 | GEO
Project description:The SARS-CoV-2 pandemic was marked with emerging viral variants, some of which were designated as variants of concern (VOCs) due to their selection and rapid circulation in the human population. Here we elucidate functional features of each VOC linked to variations in growth during infection. Patient-derived primary nasal cultures grown at air-liquid-interface (ALI) were used to model upper-respiratory infection and human lung epithelial cell lines used to model lower-respiratory infection. All VOCs replicated to higher titers than the ancestral virus, suggesting a selection for replication efficiency. In primary nasal ALI cultures, Omicron replicated to the highest titers at early time points, followed by Delta, paralleling comparative studies of patient samples. All SARS-CoV-2 viruses entered the cell primarily via a transmembrane serine protease 2 (TMPRSS2)-dependent pathway, and Omicron was more likely to use an endosomal route of entry. All VOCs activated and overcame dsRNA-activated cellular responses including interferon signaling, oligoadenylate ribonuclease L (OAS-RNase L) degradation and protein kinase R (PKR) activation. Among the VOCs Omicron expressed the most interferon and interferon stimulated genes. Infections in nasal ALI resulted in damage to nasal cells such as a compromise of cell-barrier integrity and loss of nasal cilia and ciliary beating function, especially with Delta infections. Overall, Omicron replication was optimized for growth in the upper-respiratory system and least-favorable in the lower-respiratory cell line; and Delta was the most cytopathic for both upper and lower respiratory cells. Our findings highlight the functional differences among VOCs and illuminate distinct mechanisms of pathogenesis in infected individuals.
2024-02-29 | GSE250155 | GEO
Project description:SARS-CoV-2 Omicron (B.1.1.529) and its subvariants are currently the most common variants of concern worldwide, featuring numerous mutations in the spike protein and elsewhere that collectively make Omicron more transmissible and more resistant to antibody-mediated neutralization provided by vaccination, previous infections, and monoclonal antibody therapies than its predecessors. We recently reported the creation and characterization of Ig-MS, a new mass spectrometry-based serology platform that can define the repertoire of antibodies against an antigen of interest at single proteoform resolution. Here, we applied Ig-MS to investigate the evolution of plasma antibody repertoires against the receptor-binding domain (RBD) of SARS-CoV-2 in response to the booster shot and natural viral infection. We also assessed the capacity for antibody repertoires generated in response to vaccination and/or infection with the Omicron variant to bind to both Wuhan- and Omicron-RBDs. Our results show that 1) the booster increases antibody titers against both Wuhan- and Omicron- RBDs and elicits an Omicron-specific response and 2) vaccination and infection act synergistically in generating anti-RBD antibody repertoires able to bind both Wuhan- and Omicron-RBDs with variant-specific antibodies.
2022-08-24 | MSV000090199 | MassIVE
Project description:The spike glycoprotein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mediates binding to the ACE2 receptor and subsequent membrane fusion. It exists in a range of conformations, including a closed state unable to bind the ACE2 receptor, and an open state that does so but displays more exposed antigenic surface. Spikes of variants of concern (VOCs) acquired amino acid changes linked to different opening probabilities, increased SARS-CoV-2 virulence and immune evasion. Here, using hydrogen-deuterium exchange mass spectrometry (HDX-MS), we analyzed the spike of the original Wuhan isolate, G614 mutant, spike of alpha, beta, delta and omicron VOCs and the isolated ancestral receptor binding domain (RBD) - in apo state and in complex with the ACE2 receptor. We identified changes in spike dynamics that we associated with the transition from closed to open conformation, to ACE2 binding, and to specific mutations in VOCs. We show that the RBD-associated subdomain plays a role in spike opening, whereas the NTD acts as a hotspot of conformational divergence of VOC spikes driving immune evasion. Alpha, beta and delta spikes assume predominantly open conformations and a strong ACE2 binding increases the dynamics of their core helices, priming spikes for fusion. Conversely, substitutions in omicron spike lead to predominantly binding-incompetent closed conformations, presumably enabling it to escape antibodies. At the same time, its core helices show characteristics of being pre-primed for fusion even in the absence of ACE2. These data inform on SARS-CoV-2 evolution and omicron variant emergence.
2023-03-15 | PXD039762 | Pride
Project description:During V(D)J recombination antibody diversity is enhanced by non-templated junctional modifications that generate immensely diverse heavy chain (HC) and light chain (LC) complementarity-determining 3 antigen-contact regions (CDR3s). We previously developed a mouse model that generates diverse antibody repertoires by rearranging a single human VH1-2 and Vk1-33, associated with highly diverse CDR3s generated by V(D)J recombination with mouse Ds and/or Js. Immunization of this model with SARS-CoV-2 D614G spike elicited an antibody that potently neutralized SARS-CoV-2 variants through Omicron BA.2.754. Here, we report a next generation mouse model in which a single VH1-2 rearranges to human D3-3 and JH6, generating diverse HC-CDR3s much longer on average than those of our prior model. Omicron BA.4/.5 spike ferritin nanoparticle-immunization of the new model elicited four highly-related humanized antibodies that potently neutralize downstream Omicron sub-variants. All four antibodies had 12 AA HC-CDR3s with two aromatic amino acids that engage an epitope comprising a hydrophobic patch opened-up by early omicron lineage mutations and conserved in subsequent variants. Immunization of our prior, shorter CDR3-based model, elicited slightly less potent neutralizing antibodies that bound the same Omicron epitope, and were similar in all other aspects to those from the long, fully-human CDR3 model. One tested antibody from each set reduced lung viral titers in a mouse-adapted BQ1.1 challenge. The antibodies we describe are highly related to, but more potent than, recently described antibodies from omicron-infected humans. These studies validate the utility of single human VH- and Vk-rearranging mice for discovering humanized antibodies that neutralize emerging pathogens.
2026-02-23 | E-MTAB-16106 | biostudies-arrayexpress
Project description:The Coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a global threat, exacerbated by the emergence of viral variants. Two variants of SARS-CoV-2, Omicron BA.2.75 and BA.5, led to global infection peaks between May 2022 and May 2023, yet their precise characteristics in pathogenesis are not well understood. In this study, we compared these two Omicron sublineages with the previously dominant Delta variant using a human angiotensin-converting enzyme 2 knock-in mouse model. As expected, Delta exhibited higher viral replication in the lung and brain than both Omicron sublineages which induced less severe lung damage and immune activation. In contrast, the Omicron variants especially BA.5.2 showed a propensity for cellular proliferation and developmental pathways. Both Delta and BA.5.2 variants, but not BA.2.75, led to decreased pulmonary lymphocytes, indicating differential adaptive immune response. Neuroinvasiveness was shared with all strains, accompanied by vascular abnormalities, synaptic injury, and loss of astrocytes. However, Immunostaining assays and transcriptomic analysis showed that BA.5.2 displayed stronger immune suppression and neurodegeneration, while BA.2.75 exhibited more similar characteristics to Delta in the cortex. Such differentially infectious features could be partially attributed to the weakened interaction between Omicron Spike protein and host proteomes decoded via co-immunoprecipitation followed by mass spectrometry in neuronal cells. Our present study supports attenuated replication and pathogenicity of Omicron variants but also highlights their newly infectious characteristics in the lung and brain, especially with BA.5.2 demonstrating enhanced immune evasion and neural damage that could exacerbate neurological sequelae.
2025-04-17 | GSE234799 | 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.
2023-05-10 | PXD037265 | Pride
Project description:SARS-CoV-2 infection of Lung Organoids Reveals Conserved Use of Tetraspanin-8 by Ancestral-, Delta-, and Omicron- Variants
| PRJNA870911 | ENA
Project description:To investigate the virological properties of SARS-CoV-2 variants, we amplified the clinical isolates of an early pandemic D614G-bearing isolate (B.1.1 lineage, strain TKYE610670; GISAID ID: EPI_ISL_479681), a Delta isolate (B.1.617.2 lineage, strain TKYTK1734; GISAID ID: EPI_ISL_2378732) and an Omicron isolate (BA.1 lineage, strain TY38-873; GISAID ID: EPI_ISL_7418017) and prepared the working viruses.
2022-01-07 | GSE192472 | GEO