Humoral Immune Response to SARS-CoV-2 Spike Protein Receptor-Binding Motif Linear Epitopes DOI Creative Commons
M. Monteiro, Guilherme C. Lechuga, Paloma Napoleão-Pêgo

et al.

Vaccines, Journal Year: 2024, Volume and Issue: 12(4), P. 342 - 342

Published: March 22, 2024

The worldwide spread of SARS-CoV-2 has led to a significant economic and social burden on global scale. Even though the pandemic concluded, apprehension remains regarding emergence highly transmissible variants capable evading immunity induced by either vaccination or prior infection. success viral penetration is due specific amino acid residues receptor-binding motif (RBM) involved in attachment. This region interacts with cellular receptor ACE2, triggering neutralizing antibody (nAb) response. In this study, we evaluated serum immunogenicity from individuals who received single dose combination different vaccines against original strain mutated linear RBM. Despite modest response wild-type RBM, Omicron exhibit four mutations RBM (S477N, T478K, E484A, F486V) that result even lower titers. primary immune responses observed were directed toward IgA IgG. While nAbs typically target RBD, our investigation unveiled reduced seroreactivity within RBD’s crucial subregion, deficiency may have implications for generation protective nAbs. An evaluation S1WT S2WT peptides binding using microscale thermophoresis revealed higher affinity (35 nM) sequence (GSTPCNGVEGFNCYF), which includes FNCY patch. Our findings suggest not an immunodominant vaccinated individuals. Comprehending intricate dynamics humoral response, its interplay evolution, host genetics formulating effective strategies, targeting only but also anticipating potential future coronaviruses.

Language: Английский

Virological characteristics of the SARS-CoV-2 Omicron BA.2 subvariants, including BA.4 and BA.5 DOI Creative Commons

Izumi Kimura,

Daichi Yamasoba,

Tomokazu Tamura

et al.

Cell, Journal Year: 2022, Volume and Issue: 185(21), P. 3992 - 4007.e16

Published: Sept. 14, 2022

After the global spread of SARS-CoV-2 Omicron BA.2, some BA.2 subvariants, including BA.2.9.1, BA.2.11, BA.2.12.1, BA.4, and BA.5, emerged in multiple countries. Our statistical analysis showed that effective reproduction numbers these subvariants are greater than original BA.2. Neutralization experiments revealed immunity induced by BA.1/2 infections is less against BA.4/5. Cell culture BA.2.12.1 BA.4/5 replicate more efficiently human alveolar epithelial cells particularly, fusogenic We further provided structure spike receptor-binding domain binds to ACE2 considered how substitutions play roles binding immune evasion. Moreover, using hamsters suggested pathogenic multiscale investigations suggest risk particularly BA.4/5, health

Language: Английский

Citations

248
Phenotypic evolution of SARS-CoV-2 spike during the COVID-19 pandemic DOI Creative Commons
Wilhelm Furnon, Vanessa M. Cowton, Giuditta De Lorenzo

et al.

Nature Microbiology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 3, 2025

Abstract SARS-CoV-2 variants are mainly defined by mutations in their spike. It is therefore critical to understand how the evolutionary trajectories of spike affect virus phenotypes. So far, it has been challenging comprehensively compare many spikes that emerged during pandemic a single experimental platform. Here we generated panel recombinant viruses carrying different proteins from 27 circulating between 2020 and 2024 same genomic background. We then assessed several phenotypic traits both vitro vivo. found distinct among before after emergence Omicron variants. Spike post-Omicron maintained enhanced tropism for nasal epithelium large airways but displayed, over time, typical pre-Omicron Hence, with features pre- may continue emerge future.

Language: Английский

Citations

3
Evolution of Omicron lineage towards increased fitness in the upper respiratory tract in the absence of severe lung pathology DOI Creative Commons
Arthur Wickenhagen, Meaghan Flagg, Julia R. Port

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 11, 2025

Abstract The emergence of the Omicron lineage represented a major genetic drift in SARS-CoV-2 evolution. This was associated with phenotypic changes including evasion pre-existing immunity and decreased disease severity. Continuous evolution within raised concerns potential increased transmissibility and/or To address this, we evaluate fitness pathogenesis contemporary variants XBB.1.5, XBB.1.16, EG.5.1, JN.1 upper (URT) lower respiratory tract (LRT). We compare vivo infection Syrian hamsters primary human nasal lung epithelium cells assess differences transmissibility, antigenicity, innate immune activation. replicate efficiently URT but display limited pathology lungs compared to previous fail organoids. is attenuated both LRT other fails transmit male hamster model. Our data demonstrate that has favored URT.

Language: Английский

Citations

2
Development of a Recombinant Omicron BA.1 Subunit Vaccine Candidate in Pichia pastoris DOI Creative Commons
Sibel Kalyoncu,

Dogu Sayili,

Ayça Zeybek Kuyucu

et al.

Microbial Biotechnology, Journal Year: 2025, Volume and Issue: 18(1)

Published: Jan. 1, 2025

ABSTRACT Low‐cost and safe vaccines are needed to fill the vaccine inequity gap for future pandemics. Pichia pastoris is an ideal expression system recombinant protein production due its cost‐effective easy‐to‐scale‐up process. Here, we developed a next‐generation SARS‐CoV2 Omicron BA.1‐based candidate expressed in P. . The receptor binding domain of BA.1 spike (RBD‐Omicron) was produced at 0.35 g/L supernatant. With 60% recovery after two‐step purification, RBD‐Omicron showed 99% purity. After vitro characterisation purified via chromatography, mass spectrometry, calorimetry surface plasmon resonance‐based methods, it injected into mice immunization studies. Three different doses Alum CpG adjuvanted were investigated 10 μg gave highest antigenicity. two vaccination, IgG titers serum reached more than 6 These antibodies also recognized earlier (Delta Plus: B.1.617.2) later (Eris: EG.5, Pirola: BA.2.86) variants. long‐term immunological response measured by analyzing antibody T‐cell splenocytes 60 weeks. Interestingly, Th1 significantly high even year. subvariants dominantly circulating world, so sub‐lineage‐based can be used RBD‐Omicron‐based this study suitable technology transfer transition clinic.

Language: Английский

Citations

1
Induction of the Inflammasome by the SARS‐CoV‐2 Accessory Protein ORF9b, Abrogated by Small‐Molecule ORF9b Homodimerization Inhibitors DOI
Erika Zodda, Mònica Pons, Natàlia DeMoya‐Valenzuela

et al.

Journal of Medical Virology, Journal Year: 2025, Volume and Issue: 97(2)

Published: Feb. 1, 2025

ABSTRACT Viral accessory proteins play critical roles in viral escape from host innate immune responses and inflammatory pathogenesis. Here we show that the SARS‐CoV‐2 protein, ORF9b, but not other (ORF3a, ORF3b, ORF6, ORF7, ORF8, ORF9c, ORF10), strongly activates inflammasome‐dependent caspase‐1 A549 lung carcinoma cells THP‐1 monocyte‐macrophage cells. Exposure to lipopolysaccharide (LPS) ATP additively enhanced activation of by suggesting ORF9b LPS follow parallel pathways inflammasome caspase‐1. Following rational silico approaches, have designed small molecules capable inhibiting homodimerization which experimentally inhibited ORF9b‐ORF9b homotypic interactions, caused mitochondrial eviction ORF9b‐induced cells, cytokine release restored type I interferon (IFN‐I) signaling suppressed both cell models. These are first‐in‐class compounds targeting a protein for viral‐induced exacerbated inflammation responses, with potential mitigating severe immunopathogenic damage induced highly pathogenic coronaviruses restoring antiviral curtailed infection.

Language: Английский

Citations

1
Epimaps of the SARS-CoV-2 Receptor-Binding Domain Mutational Landscape: Insights into Protein Stability, Epitope Prediction, and Antibody Binding DOI Creative Commons
Eleni Pitsillou, Assam El‐Osta, Andrew Hung

et al.

Biomolecules, Journal Year: 2025, Volume and Issue: 15(2), P. 301 - 301

Published: Feb. 18, 2025

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants poses an ongoing threat to the efficacy vaccines and therapeutic antibodies. Mutations predominantly affect receptor-binding domain (RBD) spike protein, which mediates viral entry. RBD is also a major target monoclonal antibodies that were authorised for use during pandemic. In this study, in silico approach was used investigate mutational landscape SARS-CoV-2 variants, including currently circulating Omicron subvariants. A total 40 single-point mutations assessed their potential effect on protein stability dynamics. Destabilising effects predicted such as L455S F456L, while stabilising R346T. Conformational B-cell epitope predictions subsequently performed wild-type (WT) variant RBDs. from located within residues regions found correspond sites targeted by Furthermore, homology models generated utilised protein-antibody docking. binding characteristics 10 against WT 14 evaluated. Through evaluating affinities, interactions, energy contributions residues, contributing evasion identified. findings study provide insight into structural molecular mechanisms underlying neutralising antibody evasion. Future development could focus broadly antibodies, engineering with enhanced affinity, targeting beyond RBD.

Language: Английский

Citations

1
A single inactivating amino acid change in the SARS-CoV-2 NSP3 Mac1 domain attenuates viral replication in vivo DOI Creative Commons
Taha Y. Taha,

Rahul K. Suryawanshi,

Irene P. Chen

et al.

PLoS Pathogens, Journal Year: 2023, Volume and Issue: 19(8), P. e1011614 - e1011614

Published: Aug. 31, 2023

Despite unprecedented efforts, our therapeutic arsenal against SARS-CoV-2 remains limited. The conserved macrodomain 1 (Mac1) in NSP3 is an enzyme exhibiting ADP-ribosylhydrolase activity and a possible drug target. To determine the role of Mac1 catalytic viral replication, we generated recombinant viruses replicons encoding catalytically inactive domain by mutating critical asparagine active site. While substitution to alanine (N40A) reduced ~10-fold, mutations aspartic acid (N40D) ~100-fold relative wild-type. Importantly, N40A mutation rendered unstable vitro lowered expression levels bacterial mammalian cells. When incorporated into molecular clones, N40D mutant only modestly affected fitness immortalized cell lines, but replication human airway organoids 10-fold. In mice, replicated at >1000-fold lower compared wild-type virus while inducing robust interferon response; all animals infected with survived infection. Our data validate as promising target develop antivirals.

Language: Английский

Citations

20
SARS-CoV-2 variant of concern fitness and adaptation in primary human airway epithelia DOI Creative Commons
Rita M. Meganck, Caitlin E. Edwards, Michael L. Mallory

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(4), P. 114076 - 114076

Published: April 1, 2024

The severe acute respiratory syndrome coronavirus 2 pandemic is characterized by the emergence of novel variants concern (VOCs) that replace ancestral strains. Here, we dissect complex selective pressures evaluating variant fitness and adaptation in human tissues. We evaluate viral properties host responses to reconstruct forces behind D614G through Omicron (BA.1) emergence. observe differential replication airway epithelia, differences cellular tropism, virus-induced cytotoxicity. accumulates most mutations after infection, supporting zoonosis airway. perform head-to-head competitions highest for Gamma Delta. Under these conditions, RNA recombination favors encoding B.1.617.1 lineage 3' end. Based on growth kinetics, Alpha, Gamma, Delta exhibit increased compared D614G. In contrast, global success likely derives from transmission antigenic variation. Our data provide molecular evidence support epidemiological observations VOC

Language: Английский

Citations

8
BA.1, BA.2 and BA.2.75 variants show comparable replication kinetics, reduced impact on epithelial barrier and elicit cross-neutralizing antibodies DOI Creative Commons
Janmejay Singh,

Anbalagan Anantharaj,

Aleksha Panwar

et al.

PLoS Pathogens, Journal Year: 2023, Volume and Issue: 19(2), P. e1011196 - e1011196

Published: Feb. 24, 2023

The Omicron variant of SARS-CoV-2 is capable infecting unvaccinated, vaccinated and previously-infected individuals due to its ability evade neutralization by antibodies. With multiple sub-lineages emerging in the last 12 months, there inadequate information on quantitative antibody response generated upon natural infection with whether these antibodies offer cross-protection against other variant. In this study, we characterized growth kinetics Kappa, Delta variants Calu-3 cells. Relatively higher amounts infectious virus titers, cytopathic effect disruption epithelial barrier functions was observed whereas led a more robust induction interferon pathway, lower level replication mild barrier. BA.1, BA.2 BA.2.75 were comparable cell culture subset significant increase binding neutralizing all three but lowest Finally, show that Cu 2+ , Zn Fe salts inhibited vitro RdRp activity only both culture. Thus, our results suggest high levels interferons induced may counter spread. Waning titers rendered subjects susceptible elicits can cross-react concern.

Language: Английский

Citations

14
SARS-CoV-2 omicron sub-lineages differentially modulate interferon response in human lung epithelial cells DOI Creative Commons
Gianni Gori Savellini, Gabriele Anichini, Maria Grazia Cusi

et al.

Virus Research, Journal Year: 2023, Volume and Issue: 332, P. 199134 - 199134

Published: May 17, 2023

Although most of the attention was focused on characterization changes in Spike protein among variants SARS-CoV-2 virus, mutations outside region are likely to contribute virus pathogenesis, adaptation and escape immune system. Phylogenetic analysis Omicron strains reveals that several sub-lineages could be distinguished, from BA.1 up BA.5. Regarding BA.1, BA.2 BA.5, concern viral proteins with antagonistic activity innate system, such as NSP1 (S

Language: Английский

Citations

14