Deep mutational scans for ACE2 binding, RBD expression, and antibody escape in the SARS-CoV-2 Omicron BA.1 and BA.2 receptor-binding domains

PLoS Pathogens, Journal Year: 2022, Volume and Issue: 18(11), P. e1010951 - e1010951

Published: Nov. 18, 2022

SARS-CoV-2 continues to acquire mutations in the spike receptor-binding domain (RBD) that impact ACE2 receptor binding, folding stability, and antibody recognition. Deep mutational scanning prospectively characterizes impacts of on these biochemical properties, enabling rapid assessment new seen during viral surveillance. However, effects can change as virus evolves, requiring updated deep scans. We determined all single amino acid Omicron BA.1 BA.2 RBDs ACE2-binding affinity, RBD folding, escape from binding by LY-CoV1404 (bebtelovimab) monoclonal antibody. The some differ those measured ancestral Wuhan-Hu-1 background. These epistatic shifts largely resemble previously Alpha variant due convergent epistatically modifying N501Y substitution. variants show additional lineage-specific shifts, including examples phenomenon entrenchment causes Q498R substitutions present be more favorable background than earlier strains. In contrast, substitution Q493R exhibits no sign entrenchment, with derived state, R493, being unfavorable for Wuhan-Hu-1. Likely this reason, R493Q reversion has occurred sub-variants BA.4/BA.5 BA.2.75, where affinity buffer may potentiate concurrent antigenic change. Consistent prior studies, we find have reduced expression, identify candidate stabilizing ameliorate deficit. Last, our maps highlight a broadening sites compared datasets landscape inform ongoing efforts

Language: Английский

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Compensatory epistasis maintains ACE2 affinity in SARS-CoV-2 Omicron BA.1

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Nov. 16, 2022

The Omicron BA.1 variant emerged in late 2021 and quickly spread across the world. Compared to earlier SARS-CoV-2 variants, has many mutations, some of which are known enable antibody escape. Many these antibody-escape mutations individually decrease spike receptor-binding domain (RBD) affinity for ACE2, but still binds ACE2 with high affinity. fitness evolution lineage is therefore driven by combined effects numerous mutations. Here, we systematically map epistatic interactions between 15 RBD relative Wuhan Hu-1 strain. Specifically, measure all possible combinations (2

Language: Английский

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The landscape of antibody binding affinity in SARS-CoV-2 Omicron BA.1 evolution

eLife, Journal Year: 2023, Volume and Issue: 12

Published: Feb. 13, 2023

The Omicron BA.1 variant of SARS-CoV-2 escapes convalescent sera and monoclonal antibodies that are effective against earlier strains the virus. This immune evasion is largely a consequence mutations in receptor binding domain (RBD), major antigenic target SARS-CoV-2. Previous studies have identified several key RBD leading to escape from most antibodies. However, little known about how these interact with each other RBD. Here, we systematically map interactions by measuring affinity all possible combinations 15 (2 =32,768 genotypes) 4 (LY-CoV016, LY-CoV555, REGN10987, S309) distinct epitopes. We find can lose diverse acquiring few large-effect reduce others through small-effect mutations. our results also reveal alternative pathways antibody does not include every mutation. Moreover, epistatic shown constrain decline S309 but only modestly shape landscapes Together previous work on ACE2 landscape, suggest mediated groups mutations, whose deleterious effects compensated another group (most notably Q498R N501Y).

Language: Английский

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Mutations in the SARS-CoV-2 spike receptor binding domain and their delicate balance between ACE2 affinity and antibody evasion

Protein & Cell, Journal Year: 2024, Volume and Issue: 15(6), P. 403 - 418

Published: March 4, 2024

Intensive selection pressure constrains the evolutionary trajectory of SARS-CoV-2 genomes and results in various novel variants with distinct mutation profiles. Point mutations, particularly those within receptor binding domain (RBD) spike (S) protein, lead to functional alteration both engagement monoclonal antibody (mAb) recognition. Here, we review data RBD point mutations possessed by major discuss their individual effects on ACE2 affinity immune evasion. Many single amino acid substitutions epitopes crucial for evasion capacity may conversely weaken affinity. However, this weakened effect could be largely compensated specific epistatic such as N501Y, thus maintaining overall protein all variants. The predominant direction evolution lies neither promoting nor evading mAb neutralization but a delicate balance between these two dimensions. Together, interprets how efficiently resist meanwhile is maintained, emphasizing significance comprehensive assessment mutations.

Language: Английский

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Mapping SARS-CoV-2 antigenic relationships and serological responses

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Jan. 28, 2022

During the SARS-CoV-2 pandemic, multiple variants escaping pre-existing immunity emerged, causing concerns about continued protection. Here, we use antigenic cartography to analyze patterns of cross-reactivity among a panel 21 and 15 groups human sera obtained following primary infection with 10 different or after mRNA-1273 mRNA-1273.351 vaccination. We find differences pre-Omicron caused by substitutions at spike protein positions 417, 452, 484, 501. Quantifying changes in response breadth over time additional vaccine doses, our results show largest increase between 4 weeks >3 months post-2nd dose. immunodominance regions depending on variant an individual was first exposed to, implications for risk assessment strain selection.

Language: Английский

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Different Neutralization Profiles After Primary SARS-CoV-2 Omicron BA.1 and BA.2 Infections

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: July 19, 2022

The SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) Omicron (B.1.1.529) variant is the antigenically most distinct to date. As heavily mutated spike protein enables neutralization escape, we studied serum-neutralizing activities of naïve and vaccinated individuals after BA.1 or BA.2 sub-lineage infections in live virus tests with BA.1, BA.2, wildtype (WT, B1.1), Delta (B.1.617.2) strains. Serum samples obtained WT three-dose mRNA vaccinations without prior infection were included as controls.Primary yielded reduced neutralizing antibody levels against WT, Delta, while from BA.2-infected showed almost no cross-neutralization other variants. variants was detectable vaccinations, but titers. Vaccination-breakthrough either however, generated equal cross-neutralizing all tested.Our study demonstrates that although are able enhance pre-immune individuals, primary induced mostly variant-specific antibodies, emphasizing differently shaped humoral immunity by two These data thus contribute substantially understanding responses multiple exposures different particular importance for developing vaccination strategies light future emerging

Language: Английский

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Evolution of the SARS-CoV-2 Omicron spike

Cell Reports, Journal Year: 2023, Volume and Issue: 42(12), P. 113444 - 113444

Published: Nov. 18, 2023

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern, first identified in November 2021, rapidly spread worldwide and diversified into several subvariants. spike (S) protein accumulated an unprecedented number sequence changes relative to previous variants. In this review, we discuss how S structural features modulate host cell receptor binding, virus entry, immune evasion highlight these differentiate from We also examine key properties track across the still-evolving subvariants importance continuing surveillance evolution over time.

Language: Английский

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Host immunological responses facilitate development of SARS-CoV-2 mutations in patients receiving monoclonal antibody treatments

Journal of Clinical Investigation, Journal Year: 2023, Volume and Issue: 133(6)

Published: Feb. 2, 2023

BackgroundThe role of host immunity in emergence evasive SARS-CoV-2 Spike mutations under therapeutic monoclonal antibody (mAb) pressure remains to be explored.MethodsIn a prospective, observational, monocentric ORCHESTRA cohort study, conducted between March 2021 and November 2022, mild-to-moderately ill COVID-19 patients (n = 204) receiving bamlanivimab, bamlanivimab/etesevimab, casirivimab/imdevimab, or sotrovimab were longitudinally studied over 28 days for viral loads, de novo mutations, mAb kinetics, seroneutralization against infecting variants concern, T cell immunity. Additionally, machine learning-based circulating immune-related biomarker (CIB) profile predictive was constructed confirmed an independent data set 19) that included tixagevimab/cilgavimab.ResultsPatients treated with various mAbs developed remarkable speed high specificity the targeted mAb-binding sites. Immunocompromised therapy not only continued display significantly higher but also showed likelihood developing mutations. Development escape mutants strongly correlated neutralizing capacity immunity, suggesting immune as important driver Lastly, we antiinflammatory healing-promoting milieu facilitates where 4 CIBs identified at risk accuracy.ConclusionsOur demonstrate host-driven nonimmune responses are essential development mutant SARS-CoV-2. These support point-of-care decision making reducing treatment failure improving mitigation strategies possible dissemination mutants.FundingThe project/European Union's Horizon 2020 research innovation program.

Language: Английский

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Deep mutational scans of XBB.1.5 and BQ.1.1 reveal ongoing epistatic drift during SARS-CoV-2 evolution

PLoS Pathogens, Journal Year: 2023, Volume and Issue: 19(12), P. e1011901 - e1011901

Published: Dec. 29, 2023

Substitutions that fix between SARS-CoV-2 variants can transform the mutational landscape of future evolution via epistasis. For example, large epistatic shifts in effects caused by N501Y underlied original emergence Omicron, but whether such saltations continue to define ongoing remains unclear. We conducted deep scans measure impacts all single amino acid mutations and single-codon deletions spike receptor-binding domain (RBD) on ACE2-binding affinity protein expression recent Omicron BQ.1.1 XBB.1.5 variants, we compared patterns earlier viral strains have previously profiled. As with previous scans, find many are tolerated or even enhance binding ACE2 receptor. The tolerance sites deletion largely conforms mutation. Though RBD not yet been seen dominant lineages, observe including at positions exhibit indel variation across broader sarbecovirus emerging interest, most notably well-tolerated Δ483 BA.2.86. substitutions distinguish induced as dramatic perturbations N501Y, identify drift interaction R493Q reversions 453, 455, 456, F456L defines XBB.1.5-derived EG.5 lineage. Our results highlight due epistasis, which may direct into new regions sequence space.

Language: Английский

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Understanding Mutations in Human SARS-CoV-2 Spike Glycoprotein: A Systematic Review & Meta-Analysis

Viruses, Journal Year: 2023, Volume and Issue: 15(4), P. 856 - 856

Published: March 27, 2023

Genetic variant(s) of concern (VoC) SARS-CoV-2 have been emerging worldwide due to mutations in the gene encoding spike glycoprotein. We performed comprehensive analyses protein significant variant clade SARS-CoV-2, using data available on Nextstrain server. selected various mutations, namely, A222V, N439K, N501Y, L452R, Y453F, E484K, K417N, T478K, L981F, L212I, N856K, T547K, G496S, and Y369C for this study. These were chosen based their global entropic score, emergence, spread, transmission, location receptor binding domain (RBD). The relative abundance these was mapped with mutation D614G as a reference. Our suggest rapid emergence newer alongside D614G, reported during recent waves COVID-19 parts world. could be instrumentally imperative infectivity, virulence, host immune system’s evasion SARS-CoV-2. probable impact vaccine effectiveness, antigenic diversity, antibody interactions, stability, RBD flexibility, accessibility human cell ACE2 studied silico. Overall, present study can help researchers design next generation vaccines biotherapeutics combat infection.

Language: Английский

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