Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The Receptor Binding Domain of SARS-CoV-2 Omicron Subvariants Targets Siglec-9 to Decrease the Immunogenicity by Preventing Phagocytosis of Macrophages

ABSTRACT: SARS-CoV-2 Omicron infection results in a milder clinical feature compared to the Delta strain. The development of Omicron specific vaccine has also been hampered due to the low immunogenicity. By reverse-mutating the amino acids in the Omicron receptor binding domain (RBD), we identified that the mutation from Phenylalanine 375 (F375) in the Omicron spike to Serine 375 (S375) in Delta and other early strains significantly enhances the immune response in the manner of vaccines. Interestingly, the new evolution of the 371FAPF375FAF sequence in Omicron exhibited a potent inhibitory effect on macrophage uptake of the RBD nanoparticle or spike-pseudovirus particles. Omicron RBD enhances binding to Siglec-9 on macrophages to reduce the immunogenicity and increase the immune evasion, which could be abrogated by Serine 375 mutation. Based upon these observations, we further developed a bivalent Omicron RBD with S375 mutation and Delta RBD nanoparticle vaccine, which elicited potent and broad neutralizing antibodies in mice, rabbits, and rhesus macaques. Our research suggests that manipulating the Siglec-9 pathway could be a promising approach to enhancing vaccine response. Importantly, our findings suggest that Omicron subvariants have developed a new strategy to evade immune surveillance by impairing the phagocytosis and antigen presentation processes of macrophages.

ORGANISM(S): Mus musculus

PROVIDER: GSE251973 | GEO | 2023/12/28

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Structural dynamics in the evolution of SARS-CoV-2 spike glycoprotein: HDX-MS analysis of the spike of the original Wuhan isolate, G614 spike mutant, and the isolated ancestral RBD - in apo state and in complex with the ACE2 receptor

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 | PXD039760 | Pride

Structural dynamics in the evolution of SARS-CoV-2 spike glycoprotein: HDX-MS analysis of the spike of alpha, beta, delta and omicron variants - in apo state and in complex with the ACE2 receptor

2023-03-15 | PXD039762 | Pride

Immunological and Metabolic Characteristics of the Omicron Variants Infection

Project description:The Omicron variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first identified in November 2021 in South Africa, has initiated the 5th wave of global pandemics. Here, we systemically examined immunological and metabolic characteristics of Omicron variants infection. We found Omicron resisted to neutralizing antibody targeting receptor binding domain (RBD) of wild-type SARS-CoV-2. Omicron could not be neutralized by sera of Corona Virus Disease 2019 (COVID-19) convalescent individuals who were infected with the Delta variant. Through mass spectrometry on MHC-bound peptidomes, we found that the spike protein of the Omicron variants could generate additional CD8+ T cell epitopes, compared with Delta. These epitopes could induce robust CD8+ T cell responses. Moreover, we found booster vaccination increased the cross-memory CD8+ T cell responses against Omicron. Metabolic regulome analysis of Omicron-specific T cell showed a metabolic profile that promoted memory T cell responses. Consistently, a higher fraction of memory CD8+ T cells were found in Omicron stimulated peripheral blood mononuclear cells (PBMCs). In addition, CD147 was also a receptor for the Omicron variants, and CD147 antibody inhibited infection of Omicron. CD147-mediated Omicron infection in a human CD147 transgenic mouse model induced exudative alveolar pneumonia. Taken together, our data suggested that vaccination booster and receptor blocking antibody are two effective strategies against Omicron.

2023-03-11 | PXD037955 | Pride

Distinct Core Glycan and O-Glycoform Utilization of SARS-CoV-2 Omicron Variant Spike Protein RBD Revealed by Top-Down Mass Spectrometry

Project description:The SARS-CoV-2 Omicron (B.1.1.529) variant possesses numerous spike (S) mutations particularly in the S receptor-binding domain (S-RBD) that significantly improve transmissibility and evasion of neutralizing antibodies. But exactly how the mutations in the Omicron variant enhance viral escape from immunological protection remains to be understood. The S-RBD remains the principal target for neutralizing antibodies and therapeutics, thus new structural insights into the Omicron S-RBD and characterization of the post-translational glycosylation changes can inform rational design of vaccines and therapeutics. Here we report the molecular variations and O-glycoform changes of the Omicron S-RBD variant as compared to wild-type (WA1/2020) and Delta (B.1.617.2) variants using high-resolution top-down mass spectrometry (MS). A novel O-glycosite (Thr376) unique to the Omicron variant is identified. Moreover, we have directly quantified the Core 1 and Core 2 O-glycan structures and characterized the O-glycoform structural heterogeneity of the three variants. Our findings reveal high resolution detail of Omicron O-glycoforms and their utilization to provide direct molecular evidence of proteoform alterations in the Omicron variant which could shed light on how this variant escapes immunological protection.

2022-08-08 | MSV000090098 | MassIVE

Scalable, methanol-free manufacturing of the SARS-CoV-2 receptor binding domain in engineered Komagataella phaffii

Project description:Prevention of COVID-19 on a global scale will require the continued development of high-volume, low-cost platforms for the manufacturing of vaccines to supply on-going demand. Vaccine candidates based on recombinant protein subunits remain important because they can be manufactured at low costs in existing large-scale production facilities that use microbial hosts like Komagataella phaffii (Pichia pastoris). Here, we report an improved and scalable manufacturing approach for the SARS-CoV-2 spike protein receptor binding domain (RBD); this protein is a key antigen for several reported vaccine candidates. We genetically engineered a manufacturing strain of K. phaffii to obviate the requirement for methanol-induction of the recombinant gene. Methanol-free production improved the secreted titer of the RBD protein by >5x by alleviating protein folding stress. Removal of methanol from the production process enabled scale up to a 1,200 L pre-existing production facility. This engineered strain is now used to produce an RBD-based vaccine antigen that is currently in clinical trials and could be used to produce other variants of RBD as needed for future vaccines.

2021-12-15 | GSE183408 | GEO

Human leukocyte antigen alleles associate with COVID-19 vaccine immunogenicity and risk of breakthrough infection

Project description:SARS-CoV-2 vaccine immunogenicity varies between individuals, and immune responses correlate with vaccine efficacy. Using data from 1,076 participants enrolled in ChAdOx1 nCov-19 vaccine efficacy trials in the United Kingdom, we find that inter-individual variation in normalised antibody responses against SARS-CoV-2 spike (S) and its receptor binding domain (RBD) at 28 days following first vaccination shows genome-wide significant association with major histocompatibility complex (MHC) class II alleles. The most statistically significant association with higher levels of anti-RBD antibody was HLA-DQB1*06 (P=3.2 x 10-9), which we replicate in 1,677 additional vaccinees. Individuals carrying HLA-DQB1*06 alleles were less likely to experience PCR-confirmed breakthrough infection during the Wuhan and Alpha-variant waves compared to non-carriers (HR 0.63, 0.42-0.93, P=0.02). We identify a distinct S-derived peptide that is predicted to bind effectively to HLA-DQB1*06 compared to other equivalent alleles, and find evidence of increased spike-specific memory B-cell responses in HLA-DQB1*06 carriers at 84 days post first vaccination. Our results demonstrate association of HLA type with COVID-19 vaccine antibody response and risk of breakthrough infection, with implications for future vaccine design and implementation.

| EGAS00001006909 | EGA

Mosaic RBD nanoparticle elicits immunodominant antibody responses across sarbecoviruses

Project description:Universal vaccines cross-protecting against sarbecoviruses including SARS-CoV-2 are in great need under continuous emergence of SARS-CoV-2 variants and potential novel coronavirus. Nanoparicle vaccines displaying mosaic receptor-binding domains (RBDs) or spike (S) proteins from SARS-CoV-2 and other sarbecoviruses were used for preparedness to emergent zoonotic outbreak. Here, we describe a self-assembling nanoparticle using lumazine synthase (LuS) as the scaffold to display RBDs from different sarbecoviruses. The mosaic LuS-RBD vaccines induced cross-reactive binding and neutralizing antibody responses to sarbecoviruses. Single B cell sequencing revealed that mosaic LuS-RBD elicited B-cell receptor (BCR) repertoire using an immunodominant germline gene pair of IGHV14-3: IGKV14-111 in mice. Most of the tested IGHV14-3: IGKV14-111 monoclonal antibodies (mAbs) are broadly cross-reactive to the clade 1a, 1b and 3 sarbecoviruses. By antibody binning and cryo-electron microscopy, we determined a reprensentative IGHV14-3: IGKV14-111 mAb, M2-7, bound to an conserved epitope on RBD largely overlapping with a pan-sarbecovirus mAb S2H97, which suggested that mosaic nanoparticles expended B cells recognizing the common epitopes shared by different clades of sarbecoviruses. These results provide immunological insights into the cross-reactive responses elicited by mosaic nanoparticle against emerging sarbecoviruses.

2024-05-12 | GSE240940 | GEO

Determinants of de novo B cell responses to drifted epitopes in post-vaccination SARS-CoV-2 infections data

Project description:Vaccine-induced immunity may impact subsequent de novo responses to drifted epitopes in SARS-CoV-2 variants, but this has been difficult to quantify due to the challenges in recruiting unvaccinated control groups whose first exposure to SARS-CoV-2 is a primary infection . Through local, statewide, and national SARS-CoV-2 testing programs, we were able to recruit cohorts of individuals who had recovered from either primary or post-vaccination infections by either the Delta or Omicron BA.1 variants. Regardless of variant, we observed greater Spike-specific and neutralizing antibody responses in post-vaccination infections than in those who were infected without prior vaccination. Through analysis of variant-specific memory B cells as markers of de novo responses, we observed that Delta and Omicron BA.1 infections led to a marked shift in immunodominance in which some drifted epitopes elicited minimal responses, even in primary infections. Prior immunity through vaccination had a small negative impact on these de novo responses, but this did not correlate with cross-reactive memory B cells, arguing against competitive inhibition of naïve B cells. We conclude that dampened de novo B cell responses against drifted epitopes are mostly a function of altered immunodominance hierarchies that are apparent even in primary infections, with a more modest contribution from pre-existing immunity, perhaps due to accelerated antigen clearance.

2023-09-12 | GSE242775 | GEO

Polyvalent mRNA vaccination elicited potent immune response to monkeypox surface antigens

Project description:The soaring global monkeypox cases lead to a surge in demand for monkeypox vaccine, which far exceeds the supply. mRNA vaccine has achieved great success in prevention of coronavirus disease and holds promise against diverse pathogens. In this study, we generate a polyvalent lipid nanoparticle (LNP) mRNA vaccine candidate for monkeypox virus (MPXV) and evaluate its immunogenicity in animal models. This polyvalent MPXV mRNA vaccine candidate, MPXVac-097, encodes five 2022 MPXV targets that are important surface antigens. Three-dose (prime-boost-booster) MPXVac-097 vaccination elicits strong antibody response to A35R and E8L antigens, moderate response to M1R, but not B6R or A29, highlighting the differences in immunogenicity. Bulk T cell receptor (TCR) sequencing reveals preferential usage of VJ combinations and clonal expansion of peripheral T cells after MPXVac-097 vaccination. These data demonstrate initial feasibility of developing MPXV mRNA vaccine and pave the way for its future optimization.

2023-02-13 | GSE225183 | GEO

The BNT162b2 vaccine elicits robust lymph node T follicular helper cell responses

Project description:COVID-19 mRNA vaccines generate high concentrations of circulating anti-Spike antibodies and Spike-specific CD4+ T cells following prime-boost vaccination. It is not yet clear if vaccine-induced CD4+ T cell responses in the draining lymph node contribute to this outstanding immunogenicity. Using fine needle aspiration of draining axillary lymph nodes from individuals who received the BNT162b2 mRNA vaccine, we found large populations of Spike-specific CD4+ T follicular helper cells in the draining lymph node. A broadly immunodominant HLA-DPB1*04-restricted response to Spike166-180 composes one of the largest populations of T follicular helper cells in individuals with this allele, which is itself among the most common HLA alleles in the human population. Spike-specific T follicular helper cells are present in the lymph node 30 days after vaccine boost and persist in some individuals more than 170 days. Collectively, our results underscore the key role that robust T follicular helper cell responses play in the establishment of long-term immunity in this very efficacious human vaccine.

2022-01-04 | GSE183393 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data