scholarly journals Impact of B.1.1.7 variant mutations on antibody recognition of linear SARS-CoV-2 epitopes

2021 ◽  
Author(s):  
Winston A. Haynes ◽  
Kathy Kamath ◽  
Carolina Lucas ◽  
John Shon ◽  
Akiko Iwasaki
Keyword(s):  
Immune Evasion ◽  
Large Majority ◽  
Measured Signal ◽  
Antigen Level ◽  
Spike Glycoprotein ◽  
Synonymous Mutations ◽  
Antibody Recognition ◽  
Antibody Epitope ◽  
Linear Epitopes ◽  
Dominant Epitope

In 579 COVID patient samples collected between March and July of 2020, we examined the effects of non-synonymous mutations harbored by the circulating B.1.1.7 strain on linear antibody epitope signal for spike glycoprotein and nucleoprotein. At the antigen level, the mutations only substantially reduced signal in 0.5% of the population. Although some epitope mutations reduce measured signal in up to 6% of the population, these are not the dominant epitopes for their antigens. Given dominant epitope patterns observed, our data suggest that the mutations would not result in immune evasion of linear epitopes for a large majority of these COVID patients.

scholarly journals Antibody Mapping of the Linear Epitopes of CMY-2 and SHV-1 β-Lactamases

2004 ◽  
Vol 48 (10) ◽  
pp. 3980-3988 ◽  
Author(s):  
Andrea M. Hujer ◽  
Christopher R. Bethel ◽  
Robert A. Bonomo
Keyword(s):  
Amino Acids ◽  
Polyclonal Antibodies ◽  
Synthesis Method ◽  
Hydrolytic Activity ◽  
Spot Synthesis ◽  
Antibody Recognition ◽  
Molar Excess ◽  
Omega Loop ◽  
Direct Binding ◽  
Linear Epitopes

ABSTRACT Knowledge of the amino acids that define recognition of anti-β-lactamase antibodies is critical to the interpretation of sensitivity and specificity of these antibodies when they are used in a clinical or research setting. To this end, we mapped the epitopes of the CMY-2 and SHV-1 β-lactamases by using the SPOT synthesis method. Eight linear epitopes in SHV-1 and seven linear epitopes in CMY-2 were identified by using anti-SHV-1 and anti-CMY-2 polyclonal antibodies, respectively. The epitopes of SHV-1 were mapped to amino acids at the Ambler positions ABL 28 to 38, 42 to 54, 88 to 100, 102 to 114, 170 to 182, 186 to 194, 202 to 210, and 276 to 288. In the epitope spanning amino acids 102 to 114, alanine and X-Scan analysis demonstrated that D104, Y105, P107, and S109 are essential residues for antibody recognition. In the epitope containing amino acids 170 to 182, N170, L173, P174, G175, and D176 were immunodominant. In CMY-2 β-lactamase, amino acids 4 to 16, 70 to 79, 211 to 223, 274 to 286, 289 to 298, 322 to 334, and 343 to 358 of the mature enzyme defined the major linear epitopes. A detailed analysis of the recognition sites that are located in an area analogous to the omega loop of class A β-lactamases (V211 to V223) showed that the amino acids Q215 to E219 are important in antibody binding. Incubation of CMY-2 β-lactamase with a 10-fold molar excess of anti-CMY-2 antibody for 60 min resulted in greater than 80% inhibition of nitrocefin hydrolysis. A 10-fold molar excess of anti-SHV-1 antibody reduced the activity of SHV-1 by 69%. Analysis of the CMY-2 and SHV-1 structures suggest that this reduction of hydrolytic activity may be due in part to the direct binding of antibodies to the omega loop, thereby hindering access of substrate to the active site.

scholarly journals Conformational Occlusion of Blockade Antibody Epitopes, a Novel Mechanism of GII.4 Human Norovirus Immune Evasion

mSphere ◽  
2018 ◽  
Vol 3 (1) ◽  
Author(s):  
Lisa C. Lindesmith ◽  
Michael L. Mallory ◽  
Kari Debbink ◽  
Eric F. Donaldson ◽  
Paul D. Brewer-Jensen ◽  
...  
Keyword(s):  
Immune Evasion ◽  
Particle Dynamics ◽  
Human Norovirus ◽  
Viral Pathogens ◽  
Virus Like Particles ◽  
Antibody Epitope ◽  
Binding Residues ◽  
Additional Support ◽  
Key Residues ◽  
Antibody Epitopes

In this study, we use norovirus virus-like particles to identify key residues of a conserved GII.4 blockade antibody epitope. Further, we identify an additional GII.4 blockade antibody epitope to be occluded, with antibody access governed by temperature and particle dynamics. These findings provide additional support for particle conformation-based presentation of binding residues mediated by a particle “breathing core.” Together, these data suggest that limiting antibody access to blockade antibody epitopes may be a frequent mechanism of immune evasion for GII.4 human noroviruses. Mapping blockade antibody epitopes, the interaction between adjacent epitopes on the particle, and the breathing core that mediates antibody access to epitopes provides greater mechanistic understanding of epitope camouflage strategies utilized by human viral pathogens to evade immunity.

scholarly journals Structural analysis of the Spike of the Omicron SARS-COV-2 variant by Cryo-EM and implications for immune evasion

2021 ◽  
Author(s):  
Dongchun Ni ◽  
Kelvin Lau ◽  
Priscilla Turelli ◽  
Charlene Raclot ◽  
Bertrand Beckert ◽  
...  
Keyword(s):  
South Africa ◽  
United Kingdom ◽  
Structural Analysis ◽  
High Resolution ◽  
Immune Evasion ◽  
Spike Protein ◽  
Spike Glycoprotein ◽  
The United Kingdom ◽  
New Variant ◽  
Structural Insights

The Omicron (B.1.1.529) SARS-COV-2 was reported on November 24, 2021 and declared a variant of concern a couple of days later. With its constellation of mutations acquired by this variant on its Spike glycoprotein and the speed at which this new variant has replaced the previously dominant variant Delta in South Africa and the United Kingdom, it is crucial to have atomic structural insights to reveal the mechanism of its rapid proliferation. Here we present a high-resolution cryo-EM structure of the Spike protein of the Omicron variant.

scholarly journals Non-synonymous Mutations of SARS-Cov-2 Leads Epitope Loss and Segregates its Varaints

2020 ◽  
Author(s):  
Aayatti Mallick Gupta ◽  
Sukhendu Mandal
Keyword(s):  
Amino Acid ◽  
Important Determinant ◽  
Surface Glycoprotein ◽  
Spike Glycoprotein ◽  
Synonymous Mutations ◽  
The World

Abstract The non-synonymous mutations of SARS-Cov-2 isolated from across the world have been identified during the last few months. The surface glycoprotein spike of SARS-Cov-2 forms the most important hotspot for amino acid alterations followed by the ORF1a/ORF1ab poly-proteins. It is evident that the D614G mutation in spike glycoprotein and P4715L in RdRp is the important determinant of SARS-Cov-2 evolution since its emergence. P4715L in RdRp, G251V in ORF3a and S1498F of Nsp3 is associated with the epitope loss that may influence pathogenesis caused by antibody escape variants. Phylogenomics distinguished the ancestral viral samples from China and most part of Asia, isolated between Dec, 2019 to Feb, 2020 and the evolved variants isolated from Europe and Americas from Mar, 2020 to April, 2020. The evolved variants have been found to predominant globally with the loss of epitopes from its proteins. These have implications for SARS-Cov-2 transmission, pathogenesis and immune interventions.

scholarly journals Large-scale analysis of SARS-CoV-2 spike-glycoprotein mutants demonstrates the need for continuous screening of virus isolates

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0249254
Author(s):  
Barbara Schrörs ◽  
Pablo Riesgo-Ferreiro ◽  
Patrick Sorn ◽  
Ranganath Gudimella ◽  
Thomas Bukur ◽  
...  
Keyword(s):  
Mutation Rate ◽  
Large Scale ◽  
Median Number ◽  
Spike Protein ◽  
Human Populations ◽  
Data Sets ◽  
Spike Glycoprotein ◽  
Synonymous Mutations ◽  
Different Strains ◽  
Genome Assemblies

Due to the widespread of the COVID-19 pandemic, the SARS-CoV-2 genome is evolving in diverse human populations. Several studies already reported different strains and an increase in the mutation rate. Particularly, mutations in SARS-CoV-2 spike-glycoprotein are of great interest as it mediates infection in human and recently approved mRNA vaccines are designed to induce immune responses against it. We analyzed 1,036,030 SARS-CoV-2 genome assemblies and 30,806 NGS datasets from GISAID and European Nucleotide Archive (ENA) focusing on non-synonymous mutations in the spike protein. Only around 2.5% of the samples contained the wild-type spike protein with no variation from the reference. Among the spike protein mutants, we confirmed a low mutation rate exhibiting less than 10 non-synonymous mutations in 99.6% of the analyzed sequences, but the mean and median number of spike protein mutations per sample increased over time. 5,472 distinct variants were found in total. The majority of the observed variants were recurrent, but only 21 and 14 recurrent variants were found in at least 1% of the mutant genome assemblies and NGS samples, respectively. Further, we found high-confidence subclonal variants in about 2.6% of the NGS data sets with mutant spike protein, which might indicate co-infection with various SARS-CoV-2 strains and/or intra-host evolution. Lastly, some variants might have an effect on antibody binding or T-cell recognition. These findings demonstrate the continuous importance of monitoring SARS-CoV-2 sequences for an early detection of variants that require adaptations in preventive and therapeutic strategies.

scholarly journals SARS-CoV-2 and ORF3a: Non-Synonymous Mutations and Polyproline Regions

2020 ◽  
Author(s):  
Elio Issa ◽  
Georgi Merhi ◽  
Balig Panossian ◽  
Tamara Salloum ◽  
Sima Tokajian
Keyword(s):  
Amino Acids ◽  
Immune Response ◽  
B Cell ◽  
Immune Evasion ◽  
Protein Sequences ◽  
B Cell Epitopes ◽  
Synonymous Mutations ◽  
Viral Spread ◽  
Rapid Accumulation ◽  
The Impact

AbstractThe effect of the rapid accumulation of non-synonymous mutations on the pathogenesis of SARS-CoV-2 is not yet known. To predict the impact of non-synonymous mutations and polyproline regions identified in ORF3a on the formation of B-cell epitopes and their role in evading the immune response, nucleotide and protein sequences of 537 available SARS-CoV-2 genomes were analyzed for the presence of non-synonymous mutations and polyproline regions. Mutations were correlated with changes in epitope formation. A total of 19 different non-synonymous amino acids substitutions were detected in ORF3a among 537 SARS-CoV-2 strains. G251V was the most common and identified in 9.9% (n=53) of the strains and was predicted to lead to the loss of a B-cell like epitope in ORF3a. Polyproline regions were detected in two strains (EPI_ISL_410486, France and EPI_ISL_407079, Finland) and affected epitopes formation. The accumulation of non-synonymous mutations and detected polyproline regions in ORF3a of SARS-CoV-2 could be driving the evasion of the host immune response thus favoring viral spread. Rapid mutations accumulating in ORF3a should be closely monitored throughout the COVID-19 pandemic.ImportanceAt the surge of the COVID-19 pandemic and after three months of the identification of SARS-CoV-2 as the disease-causing pathogen, nucleic acid changes due to host-pathogen interactions are insightful into the evolution of this virus. In this paper, we have identified a set of non-synonymous mutations in ORF3a and predicted their impact on B-cell like epitope formation. The accumulation of non-synonymous mutations in ORF3a could be driving protein changes that mediate immune evasion and favoring viral spread.

scholarly journals dN/dS dynamics quantify tumour immunogenicity and predict response to immunotherapy

2020 ◽  
Author(s):  
Luis Zapata ◽  
Giulio Caravagna ◽  
Marc J Williams ◽  
Eszter Lakatos ◽  
Khalid AbdulJabbar ◽  
...  
Keyword(s):  
Clinical Response ◽  
Patient Outcomes ◽  
Immune Evasion ◽  
Cancer Evolution ◽  
Immune Selection ◽  
Primary Tumors ◽  
Synonymous Mutations ◽  
Evolutionary Genomic ◽  
Tumor Immunogenicity ◽  
Pre Treatment

AbstractImmunoediting is a major force during cancer evolution that selects for clones with low immunogenicity (adaptation), or clones with mechanisms of immune evasion (escape). However, quantifying immunogenicity in the cancer genome and how the tumour-immune coevolutionary dynamics impact patient outcomes remain unexplored. Here we show that the ratio of nonsynonymous to synonymous mutations (dN/dS) in the immunopeptidome quantifies tumor immunogenicity and differentiates between adaptation and escape. We analysed 8,543 primary tumors from TCGA and validated immune dN/dS as a measure of selection associated with immune infiltration in immune-adapted tumours. In a cohort of 308 metastatic patients that received immunotherapy, pre-treatment lesions in non-responders showed increased immune selection (dN/dS<1), whereas responders did not and instead harboured a higher proportion of genetic escape mechanisms. Ultimately, these findings highlight the potential of evolutionary genomic measures to predict clinical response to immunotherapy.

scholarly journals Spike Protein NTD mutation G142D in SARS-CoV-2 Delta VOC lineages is associated with frequent back mutations, increased viral loads, and immune evasion

2021 ◽  
Author(s):  
Lishuang Shen ◽  
Timothy J. Triche ◽  
Jennifer Dien Bard ◽  
Jaclyn A. Biegel ◽  
Alexander R. Judkins ◽  
...  
Keyword(s):  
Viral Load ◽  
Immune Evasion ◽  
Neutralizing Antibodies ◽  
Amino Acid Position ◽  
Spike Protein ◽  
Multiple Time ◽  
Viral Neutralization ◽  
Antibody Recognition ◽  
Recurrent Mutations ◽  
Multiple Time Points

AbstractThe significantly greater infectivity of the SARS-CoV-2 Delta variants of concern (VOC) is hypothesized to be driven by key mutations that result in increased transmissibility, viral load and/or evasion of host immune response. We surveyed the mutational profiles of Delta VOC genomes between September 2020 and mid-August 2021 and identified a previously unreported mutation pattern at amino acid position 142 in the N-terminal domain (NTD) of the spike protein which demonstrated multiple rounds of mutation from G142 to D142 and back. This pattern of frequent back mutations was observed at multiple time points and across Delta VOC sub-lineages. The etiology for these recurrent mutations is unclear but raises the possibility of host-directed editing of the SARS-CoV-2 genome. Within Delta VOC this mutation is associated with higher viral load, further enhanced in the presence of another NTD mutation (T95I) which was also frequently observed in these cases. Protein modeling of both mutations predicts alterations of the surface topography of the NTD by G142D, specifically disturbance of the ‘super site’ epitope that binds NTD-directed neutralizing antibodies (NAbs). The appearance of frequent and repeated G142D followed by D142G back mutations is previously unreported in SARS-CoV-2 and may represent viral adaptation to evolving host immunity characterized by increasing frequency of spike NAbs, from both prior infection and vaccine-based immunity. The emergence of alterations of the NTD in and around the main NAb epitope is a concerning development in the ongoing evolution of SARS-CoV-2 which may contribute to increased infectivity, immune evasion and ‘breakthrough infections’ characteristic of Delta VOC. Future vaccine and therapy development may benefit by recognizing the emergence of these novel spike NTD mutations and considering their impact on antibody recognition, viral neutralization, infectivity, replication, and viral load.

scholarly journals Emergence of a recurrent insertion in the N-terminal domain of the SARS-CoV-2 spike glycoprotein

2021 ◽  
Author(s):  
Marco Gerdol
Keyword(s):  
Neutralizing Antibodies ◽  
Immune Escape ◽  
Progressive Increase ◽  
Spike Glycoprotein ◽  
Synonymous Mutations ◽  
Terminal Domain ◽  
Surveillance Programs ◽  
Key Sites ◽  
Partial Overlap ◽  
Antibody Epitopes

Tracking the evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through genomic surveillance programs is undoubtedly one of the key priorities in the current pandemic situation. Although the genome of SARS-CoV-2 acquires mutations at a slower rate compared with other RNA viruses, evolutionary pressures derived from the widespread circulation of SARS-CoV-2 in the human population have progressively favored the global emergence though natural selection of several variants of concern that carry multiple non-synonymous mutations in the spike glycoprotein. Such mutations are often placed in key sites within major antibody epitopes and may therefore confer resistance to neutralizing antibodies, leading to partial immune escape, or otherwise compensate minor infectivity deficits associated with other mutations. As previously shown by other authors, several emerging variants carry recurrent deletion regions (RDRs) that display a partial overlap with antibody epitopes located in the spike N-terminal domain. Comparatively, very little attention has been directed towards spike insertion mutations, which often go unnoticed due to the use of insertion-unaware bioinformatics analysis pipelines. This manuscript describe a single recurrent insertion region (RIR1) in the N-terminal domain of SARS-CoV-2 spike protein, characterized by the independent acquisition of 3-4 additional codons between Arg214 and Asp215 in different viral lineages. Even though RIR1 is unlikely to confer antibody escape, its progressive increase in frequency and its association with two distinct emerging lineages (A.2.5 and B.1.214.2) warrant further investigation concerning its effects on spike structure and viral infectivity.

scholarly journals Functional properties of the spike glycoprotein of the emerging SARS-CoV-2 variant B.1.1.529

2021 ◽  
Author(s):  
Qian Wang ◽  
Saumya Anang ◽  
Sho Iketani ◽  
Yicheng Guo ◽  
Lihong Liu ◽  
...  
Keyword(s):  
Virus Infection ◽  
Functional Properties ◽  
Immune Evasion ◽  
Low Temperatures ◽  
Syncytium Formation ◽  
The Other ◽  
Spike Glycoprotein ◽  
Virus Particles ◽  
Cytopathic Effects

The recently emerged B.1.1.529 (Omicron) SARS-CoV-2 variant has a highly divergent spike (S) glycoprotein. We compared the functional properties of B.1.1.529 S with those of previous globally prevalent SARS-CoV-2 variants, D614G and B.1.617.2. Relative to these variants, B.1.1.529 S exhibits decreased processing, resulting in less efficient syncytium formation and lower S incorporation into virus particles. Nonetheless, B.1.1.529 S supports virus infection equivalently. B.1.1.529 and B.1.617.2 S glycoproteins bind ACE2 with higher affinity than D614G S. The unliganded B.1.1.529 S trimer is less stable at low temperatures than the other SARS-CoV-2 spikes, a property related to spike conformation. Upon ACE2 binding, the B.1.1.529 S trimer sheds S1 at 37 degrees but not at 0 degrees C. B.1.1.529 pseudoviruses are relatively resistant to neutralization by sera from convalescent COVID-19 patients and vaccinees. These properties of the B.1.1.529 spike glycoprotein likely influence the transmission, cytopathic effects and immune evasion of this emerging variant.

Sign in / Sign up

Export Citation Format

Share Document