Omicron Spike confers enhanced infectivity and interferon resistance to SARS-CoV-2 in human nasal tissue

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 30, 2024

Omicron emerged following COVID-19 vaccination campaigns, displaced previous SARS-CoV-2 variants of concern worldwide, and gave rise to lineages that continue spread. Here, we show exhibits increased infectivity in primary adult upper airway tissue relative Delta. Using recombinant forms nasal epithelial cells cultured at the liquid-air interface, mutations unique Spike enable enhanced entry into tissue. Unlike earlier SARS-CoV-2, our findings suggest enters independently serine transmembrane proteases instead relies upon metalloproteinases catalyze membrane fusion. Furthermore, demonstrate this pathway unlocked by enables evasion from constitutive interferon-induced antiviral factors restrict attachment. Therefore, transmissibility exhibited humans may be attributed not only its vaccine-elicited adaptive immunity, but also superior invasion epithelia resistance cell-intrinsic barriers present therein.

Language: Английский

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Viral Membrane Fusion: A Dance Between Proteins and Lipids

Annual Review of Virology, Journal Year: 2023, Volume and Issue: 10(1), P. 139 - 161

Published: Sept. 29, 2023

There are at least 21 families of enveloped viruses that infect mammals, and many contain members high concern for global human health. All have a dedicated fusion protein or complex enacts the critical genome-releasing membrane event is essential before viral replication within host cell interior can begin. Because all enter cells by fusion, it behooves us to know how proteins function. Viral also major targets neutralizing antibodies, hence they serve as key vaccine immunogens. Here we review current concepts about focusing on triggered, structural intermediates between pre- postfusion forms, their interplay with lipid bilayers engage. We discuss cellular therapeutic interventions thwart virus-cell fusion.

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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Antigenic evolution of SARS coronavirus 2

Current Opinion in Virology, Journal Year: 2023, Volume and Issue: 62, P. 101349 - 101349

Published: Aug. 28, 2023

SARS coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, emerged in China December 2019. Vaccines developed were very effective initially, however, virus has shown remarkable evolution with multiple variants spreading globally over last three years. Nowadays, newly emerging Omicron lineages are gaining substitutions at a fast rate, resulting escape from neutralization by antibodies that target Spike protein. Tools to map impact on further antigenic SARS-CoV-2, such as cartography, may be helpful update SARS-CoV-2 vaccines. In this review, we focus highlighting protein individually and combination immune escape.

Language: Английский

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SARS-CoV-2 omicron BA.5 and XBB variants have increased neurotropic potential over BA.1 in K18-hACE2 mice and human brain organoids

Frontiers in Microbiology, Journal Year: 2023, Volume and Issue: 14

Published: Nov. 23, 2023

The reduced pathogenicity of the omicron BA.1 sub-lineage compared to earlier variants is well described, although whether such attenuation retained for later like BA.5 and XBB remains controversial. We show that isolates were significantly more pathogenic in K18-hACE2 mice than a isolate, showing increased neurotropic potential, resulting fulminant brain infection mortality, similar seen original ancestral isolates. also infected human cortical organoids greater extent In brains mice, neurons main target infection, neuronal progenitor cells immature infected. results herein suggest evolving may have increasing potential.

Language: Английский

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Nanomolar anti-SARS-CoV-2 Omicron activity of the host-directed TMPRSS2 inhibitor N-0385 and synergistic action with direct-acting antivirals

Antiviral Research, Journal Year: 2024, Volume and Issue: 225, P. 105869 - 105869

Published: March 26, 2024

SARS-CoV-2 Omicron subvariants with increased transmissibility and immune evasion are spreading globally alarming persistence. Whether the mutations evolution of spike (S) alter viral hijacking human TMPRSS2 for entry remains to be elucidated. This is particularly important investigate because large number diversity S reported since emergence BA.1. Here we report that a molecular determinant all clinical isolates tested in lung cells, including ancestral (BA.1, BA.2, BA.5), contemporary (BQ.1.1, XBB.1.5, EG.5.1) currently circulating BA.2.86. First, used co-transfection assay demonstrate endoproteolytic cleavage by subvariants. Second, found N-0385, highly potent inhibitor, robust inhibitor virus-like particles harbouring protein Third, show N-0385 exhibits nanomolar broad-spectrum antiviral activity against live Calu-3 cells primary patient-derived bronchial epithelial cells. Interestingly, 10-20 times more than repositioned camostat, BA.5, EG.5.1, We further shows broad synergistic clinically approved direct-acting antivirals (DAAs), i.e., remdesivir nirmatrelvir, subvariants, demonstrating potential therapeutic benefits multi-targeted treatment based on DAAs.

Language: Английский

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Functional and antigenic characterization of SARS-CoV-2 spike fusion peptide by deep mutational scanning

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: May 14, 2024

Abstract The fusion peptide of SARS-CoV-2 spike protein is functionally important for membrane during virus entry and part a broadly neutralizing epitope. However, sequence determinants at the its adjacent regions pathogenicity antigenicity remain elusive. In this study, we perform series deep mutational scanning (DMS) experiments on an S2 region spanning authentic in different cell lines presence antibodies. We identify mutations residue 813 that reduced TMPRSS2-mediated with decreased virulence. addition, show F823Y mutation, present bat betacoronavirus HKU9 protein, confers resistance to Our findings provide mechanistic insights into also highlight potential challenge developing protective S2-based coronavirus vaccines.

Language: Английский

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The proton-activated chloride channel inhibits SARS-CoV-2 spike protein-mediated viral entry through the endosomal pathway.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 13, 2025

SARS-CoV-2 binds to its obligatory receptor, angiotensin-converting enzyme 2 (ACE2) and capitalizes on decreasing endosomal acidity cathepsin-mediated spike protein cleavage enter cells. Endosomal acidification is driven by V-ATPase which pumps protons (H + ) into the lumen. The driving force for H maintained import of chloride (Cl - mediated intracellular CLC transporters. We have recently identified Proton-Activated Chloride (PAC) channel as a negative regulator acidification. PAC responds low pH releases Cl from lumen prevent hyperacidification. However, role in viral entry remains unexplored. Here, we show that overexpressing ACE2 expressing HEK 293T cells markedly inhibited spike-mediated entry. Several lines evidence suggest this effect was due suppression pathway. First, abilities regulate inhibit pseudoviral were both dependent localization activity. Second, inhibitory similar E64-d, cathepsin inhibitor, while no major additive treatments observed. Third, inhibition also attenuated TMPRSS2, provides alternative pathway through cell surface. Importantly, overexpression number size plaques formed two live isolates (B.1 Omicron XBB.1.16) Vero E6 Altogether, our data indicates plays vital inhibiting identifies potential novel target against infection other viruses, rely

Language: Английский

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SARS-CoV-2 Spike-Mediated Entry and Its Regulation by Host Innate Immunity

Viruses, Journal Year: 2023, Volume and Issue: 15(3), P. 639 - 639

Published: Feb. 27, 2023

The constantly evolving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC) fuel the worldwide disease (COVID-19) pandemic. spike protein is essential for SARS-CoV-2 viral entry and thus has been extensively targeted by therapeutic antibodies. However, mutations along in VOC Omicron subvariants have caused more rapid spread strong antigenic drifts, rendering most current antibodies ineffective. Hence, understanding targeting molecular mechanism activation great interest curbing development new approaches. In this review, we summarize conserved features spike-mediated various highlight converging proteolytic processes involved priming activating spike. We also roles innate immune factors preventing spike-driven membrane fusion provide outlines identification novel therapeutics against infections.

Language: Английский

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The SARS-CoV-2 Spike is a virulence determinant and plays a major role on the attenuated phenotype of Omicron virus in a feline model of infection

Journal of Virology, Journal Year: 2024, Volume and Issue: 98(3)

Published: Feb. 29, 2024

The role of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.1 Spike (S) on disease pathogenesis was investigated. For this, we generated recombinant viruses harboring S D614G mutation (rWA1-D614G) and gene (rWA1-Omi-S) in backbone ancestral SARS-CoV-2 WA1 strain genome. were characterized

Language: Английский

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