ACE2-binding exposes the SARS-CoV-2 fusion peptide to broadly neutralizing coronavirus antibodies

Science, Год журнала: 2022, Номер 377(6607), С. 735 - 742

Опубликована: Июль 12, 2022

The coronavirus spike glycoprotein attaches to host receptors and mediates viral fusion. Using a broad screening approach, we isolated seven monoclonal antibodies (mAbs) that bind all human-infecting proteins from severe acute respiratory syndrome 2 (SARS-CoV-2) immune donors. These mAbs recognize the fusion peptide acquire affinity breadth through somatic mutations. Despite targeting conserved motif, only some show neutralizing activity in vitro against alpha- betacoronaviruses, including animal coronaviruses WIV-1 PDF-2180. Two selected also neutralize Omicron BA.1 BA.2 authentic viruses reduce burden pathology vivo. Structural functional analyses showed peptide–specific bound with different modalities cryptic epitope hidden prefusion stabilized spike, which became exposed upon binding of angiotensin-converting enzyme (ACE2) or ACE2-mimicking mAbs.

Язык: Английский

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Structural and functional impact by SARS-CoV-2 Omicron spike mutations

Cell Reports, Год журнала: 2022, Номер 39(4), С. 110729 - 110729

Опубликована: Апрель 1, 2022

Язык: Английский

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

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Ноя. 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

Язык: Английский

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Selection Analysis Identifies Clusters of Unusual Mutational Changes in Omicron Lineage BA.1 That Likely Impact Spike Function

Molecular Biology and Evolution, Год журнала: 2022, Номер 39(4)

Опубликована: Март 16, 2022

Among the 30 nonsynonymous nucleotide substitutions in Omicron S-gene are 13 that have only rarely been seen other SARS-CoV-2 sequences. These mutations cluster within three functionally important regions of at sites will likely impact (1) interactions between subunits Spike trimer and predisposition to shift from down up configurations, (2) with ACE2 receptors, (3) priming for membrane fusion. We show here that, based on both rarity these intrapatient sequencing reads patterns selection codon where occur related sarbecoviruses, prior emergence would predicted decrease fitness any virus which they occurred. further propose each clusters therefore cooperatively interact mitigate their individual costs, and, combination mutations, adaptively alter function Spike. Given evident epidemic growth advantages overall previously known lineages, it is crucial determine how such complex highly adaptive mutation constellations were assembled S-gene, why, despite unprecedented global genomic surveillance efforts, early stages this assembly process went completely undetected.

Язык: Английский

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Cryo-EM structures of SARS-CoV-2 Omicron BA.2 spike

Cell Reports, Год журнала: 2022, Номер 39(13), С. 111009 - 111009

Опубликована: Июнь 1, 2022

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.2 sub-lineage has gained in proportion relative to BA.1. Because spike (S) protein variations may underlie differences their pathobiology, here we determine cryoelectron microscopy (cryo-EM) structures of the S ectodomain and compare these with previously determined BA.1 structures. receptor-binding domain (RBD) mutations induce remodeling RBD structure, resulting tighter packing improved thermostability. Interprotomer interactions are enhanced closed (or 3-RBD-down) S, while fusion peptide is less accessible antibodies than Binding pseudovirus neutralization assays reveal extensive immune evasion defining epitopes two outer face-binding antibodies, DH1044 DH1193, that neutralize both BA.2. Taken together, our results indicate stabilization state through interprotomer RBD-RBD a hallmark variant show key functional regions proteins.

Язык: Английский

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Omicron variant (B.1.1.529) and its sublineages: What do we know so far amid the emergence of recombinant variants of SARS-CoV-2?

Biomedicine & Pharmacotherapy, Год журнала: 2022, Номер 154, С. 113522 - 113522

Опубликована: Авг. 15, 2022

Since the start of COVID-19 pandemic, numerous variants SARS-CoV-2 have been reported worldwide. The advent concern (VOCs) raises severe concerns amid serious containment efforts against that include physical measures, pharmacological repurposing, immunization, and genomic/community surveillance. Omicron variant (B.1.1.529) has identified as a highly modified, contagious, crucial among five VOCs SARS-CoV-2. increased affinity spike protein (S-protein), host receptor, angiotensin converting enzyme-2 (ACE-2), due to higher number mutations in receptor-binding domain (RBD) S-protein proposed primary reason for decreased efficacy majorly available vaccines transmissible nature variant. Because its significant competitive advantage, sublineages swiftly surpassed other become dominant circulating lineages nations. prevalent strain United Kingdom South Africa. Furthermore, emergence recombinant through conjunction with or by mixing variant's sublineages/subvariants poses major threat humanity. This various issues hazards regarding sublineages, such an breakout susceptible populations fully vaccinated persons. As result, understanding features genetic implications this is crucial. Hence, we explained depth evolution analyzed repercussions on infectiousness, dissemination ability, viral entry mechanism, immune evasion. We also presented viewpoint feasible strategies precluding counteracting any future catastrophic spread omicron could result detrimental wave cases.

Язык: Английский

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Bibliometric Analysis of Publications on the Omicron Variant from 2020 to 2022 in the Scopus Database Using R and VOSviewer

International Journal of Environmental Research and Public Health, Год журнала: 2022, Номер 19(19), С. 12407 - 12407

Опубликована: Сен. 29, 2022

Human respiratory infections caused by coronaviruses can range from mild to deadly. Although there are numerous studies on coronavirus disease 2019 (COVID-19), few have been published its Omicron variant. In order remedy this deficiency, study undertook a bibliometric analysis of the publishing patterns variant and identified hotspots. Automated transportation, environmental protection, improved healthcare, innovation in banking, smart homes just areas where machine learning has found use tackling complicated problems. The sophisticated Scopus database was queried for papers with term "Omicron" title between January 2020 June 2022. Microsoft Excel 365, VOSviewer, Bibliometrix, Biblioshiny R were used statistical publications. Over period, 1917 relevant publications database. Viruses most popular research, 150 published, while Cell cited source. determined productive nations, USA leading list highest number (344) level international collaboration This highlights scientific advances scholarly trends serves as model demonstrating global research. It aid policymakers medical researchers fully grasp current status research also provides normative data visualization, study, application.

Язык: Английский

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Atlas of currently available human neutralizing antibodies against SARS-CoV-2 and escape by Omicron sub-variants BA.1/BA.1.1/BA.2/BA.3

Immunity, Год журнала: 2022, Номер 55(8), С. 1501 - 1514.e3

Опубликована: Июнь 15, 2022

SARS-CoV-2 Omicron variant has presented significant challenges to current antibodies and vaccines. Herein, we systematically compared the efficacy of 50 human monoclonal (mAbs), covering seven identified epitope classes RBD, against sub-variants BA.1, BA.1.1, BA.2, BA.3. Binding pseudovirus-based neutralizing assays revealed that 37 mAbs lost activities, whereas others displayed variably decreased activities four sub-variants. BA.2 was found be more sensitive RBD-5 than other Furthermore, a quaternary complex structure BA.1 RBD with three showing different potencies provided basis for understanding immune evasion lack G446S mutation accounting sensitivity mAbs. Our results may guide application available facilitate development universal therapeutic vaccines COVID-19.

Язык: Английский

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Essential role of TMPRSS2 in SARS-CoV-2 infection in murine airways

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Окт. 15, 2022

Abstract In cultured cells, SARS-CoV-2 infects cells via multiple pathways using different host proteases. Recent studies have shown that the furin and TMPRSS2 (furin/TMPRSS2)-dependent pathway plays a minor role in infection of Omicron variant. Here, we confirm uses furin/TMPRSS2-dependent inefficiently enters mainly cathepsin-dependent endocytosis TMPRSS2-expressing VeroE6/TMPRSS2 Calu-3 cells. This is case despite efficient cleavage spike protein Omicron. However, airways TMPRSS2-knockout mice, significantly reduced. We furthermore show propagation mouse-adapted QHmusX strain human clinical isolates Beta Gamma reduced mice. Therefore, variant isn’t an exception vivo, analysis with mice important when evaluating variants. conclusion, this study shows critically for murine airways, including

Язык: Английский

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Determinants of Spike infectivity, processing, and neutralization in SARS-CoV-2 Omicron subvariants BA.1 and BA.2

Cell Host & Microbe, Год журнала: 2022, Номер 30(9), С. 1255 - 1268.e5

Опубликована: Июль 18, 2022

SARS-CoV-2 Omicron rapidly outcompeted other variants and currently dominates the COVID-19 pandemic. Its enhanced transmission immune evasion are thought to be driven by numerous mutations in Spike protein. Here, we systematically introduced BA.1 and/or BA.2 into ancestral protein examined impacts on function, processing, susceptibility neutralization. Individual of S371F/L, S375F, T376A ACE2-receptor-binding domain as well Q954H N969K hinge region 1 impaired infectivity, while changes G339D, D614G, N764K, L981F moderately it. Most N-terminal receptor-binding reduced sensitivity neutralization sera from individuals vaccinated with BNT162b2 vaccine therapeutic antibodies. Our results represent a systematic functional analysis adaptations that have allowed this variant dominate current

Язык: Английский

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