SARS-CoV-2 variant biology: immune escape, transmission and fitness

Nature Reviews Microbiology, Год журнала: 2023, Номер unknown

Опубликована: Янв. 18, 2023

In late 2020, after circulating for almost a year in the human population, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibited major step change its adaptation to humans. These highly mutated forms of SARS-CoV-2 had enhanced rates transmission relative previous variants and were termed 'variants concern' (VOCs). Designated Alpha, Beta, Gamma, Delta Omicron, VOCs emerged independently from one another, turn each rapidly became dominant, regionally or globally, outcompeting variants. The success VOC previously dominant variant was enabled by altered intrinsic functional properties virus and, various degrees, changes antigenicity conferring ability evade primed immune response. increased fitness associated with is result complex interplay biology context changing immunity due both vaccination prior infection. this Review, we summarize literature on transmissibility variants, role mutations at furin spike cleavage site non-spike proteins, potential importance recombination success, evolution T cells, innate population immunity. shows complicated relationship among antigenicity, virulence, which has unpredictable implications future trajectory disease burden COVID-19.

Язык: Английский

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SARS-CoV-2 biology and host interactions

Nature Reviews Microbiology, Год журнала: 2024, Номер 22(4), С. 206 - 225

Опубликована: Янв. 15, 2024

Язык: Английский

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Spike mutations contributing to the altered entry preference of SARS-CoV-2 omicron BA.1 and BA.2

Emerging Microbes & Infections, Год журнала: 2022, Номер 11(1), С. 2275 - 2287

Опубликована: Авг. 30, 2022

SARS-CoV-2 B.1.1.529.1 (Omicron BA.1) emerged in November 2021 and quickly became the predominant circulating variant globally. Omicron BA.1 contains more than 30 mutations spike protein, which contribute to its altered virological features when compared ancestral or previous variants. Recent studies by us others demonstrated that is less dependent on transmembrane serine protease 2 (TMPRSS2), efficient cleavage, fusogenic, adopts an propensity utilize plasma membrane endosomal pathways for virus entry. Ongoing suggest these of are part retained subsequent sublineages. However, exact determinants remain incompletely understood. In this study, we investigated observed characteristics Omicron. By screening individual changes BA.2 spike, identify 69-70 deletion, E484A, H655Y reduced TMPRSS2 usage while 25-27 S375F, T376A result cleavage. Among shared BA.2, S375F reduce spike-mediated fusogenicity. Interestingly, change consistently reduces increases use proteases. keeping with findings, substitution alone entry facilitates WT. Overall, our study identifies key contributes understanding determinant pathogenicity

Язык: Английский

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SARS-CoV-2 and innate immunity: the good, the bad, and the “goldilocks”

Cellular and Molecular Immunology, Год журнала: 2023, Номер 21(2), С. 171 - 183

Опубликована: Ноя. 20, 2023

Abstract An ancient conflict between hosts and pathogens has driven the innate adaptive arms of immunity. Knowledge about this interplay can not only help us identify biological mechanisms but also reveal pathogen vulnerabilities that be leveraged therapeutically. The humoral response to SARS-CoV-2 infection been focus intense research, role immune system received significantly less attention. Here, we review current knowledge various means employs evade defense systems. We consider immunity in vaccines phenomenon long COVID.

Язык: Английский

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Therapeutic and vaccine-induced cross-reactive antibodies with effector function against emerging Omicron variants

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Янв. 17, 2023

Currently circulating SARS-CoV-2 variants acquired convergent mutations at receptor-binding domain (RBD) hot spots 1 . Their impact on viral infection, transmission, and efficacy of vaccines therapeutics remains poorly understood. Here, we demonstrate that recently emerged BQ.1.1. XBB.1 bind ACE2 with high affinity promote membrane fusion more efficiently than earlier Omicron variants. Structures the BQ.1.1 RBDs bound to human S309 Fab (sotrovimab parent) explain altered recognition preserved antibody binding through conformational selection. We show sotrovimab binds avidly all variants, promotes Fc-dependent effector functions protects mice challenged BQ.1.1, variant displaying greatest loss neutralization. Moreover, in several donors vaccine-elicited plasma antibodies cross-react trigger against despite reduced neutralizing activity. Cross-reactive RBD-directed memory B cells remained dominant even after two exposures spikes, underscoring persistent immune imprinting. Our findings suggest this previously overlooked class cross-reactive antibodies, exemplified by S309, may contribute protection disease caused emerging elicitation functions.

Язык: Английский

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High-throughput identification of prefusion-stabilizing mutations in SARS-CoV-2 spike

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Апрель 10, 2023

Designing prefusion-stabilized SARS-CoV-2 spike is critical for the effectiveness of COVID-19 vaccines. All vaccines in US encode with K986P/V987P mutations to stabilize its prefusion conformation. However, contemporary methods on engineering immunogens involve tedious experimental work and heavily rely structural information. Here, we establish a systematic unbiased method identifying that concomitantly improve expression conformation spike. Our integrates fluorescence-based fusion assay, mammalian cell display technology, deep mutational scanning. As proof-of-concept, apply this region S2 domain includes first heptad repeat central helix. results reveal besides K986P V987P, several simultaneously significantly lower fusogenicity stabilization common challenge viral immunogen design, will help accelerate vaccine development against different viruses.

Язык: Английский

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Spike N354 glycosylation augments SARS-CoV-2 fitness for human adaptation through structural plasticity

National Science Review, Год журнала: 2024, Номер 11(7)

Опубликована: Июнь 13, 2024

ABSTRACT Selective pressures have given rise to a number of SARS-CoV-2 variants during the prolonged course COVID-19 pandemic. Recently evolved differ from ancestors in additional glycosylation within spike protein receptor-binding domain (RBD). Details how acquisition impacts viral fitness and human adaptation are not clearly understood. Here, we dissected role N354-linked glycosylation, acquired by BA.2.86 sub-lineages, as RBD conformational control element attenuating infectivity. The reduced infectivity is recovered presence heparin sulfate, which targets ‘N354 pocket’ ease restrictions transition resulting ‘RBD-up’ state, thereby conferring an adjustable Furthermore, N354 improved cleavage cell–cell fusion, particular escaped one subset ADCC antibodies. Together with immunogenicity hybrid immunity background, these indicate single amino acid event provides selective advantage humans through multiple mechanisms.

Язык: Английский

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Single-molecule imaging reveals allosteric stimulation of SARS-CoV-2 spike receptor binding domain by host sialic acid

Science Advances, Год журнала: 2024, Номер 10(29)

Опубликована: Июль 17, 2024

Conformational dynamics of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (S) mediate exposure binding site for cellular receptor, angiotensin-converting enzyme (ACE2). The N-terminal domain (NTD) S binds terminal sialic acid (SA) moieties on cell surface, but functional role this interaction in virus entry is unknown. Here, we report that NTD-SA enhances both S-mediated attachment and ACE2 binding. Through single-molecule Förster resonance energy transfer imaging individual trimers, demonstrate SA to NTD allosterically shifts conformational equilibrium, favoring enhanced ACE2-binding site. Antibodies target block binding, which contributes their mechanism neutralization. These findings inform mechanisms activation at surface.

Язык: Английский

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Evolutionary remodelling of N‐terminal domain loops fine‐tunes SARS‐CoV‐2 spike

EMBO Reports, Год журнала: 2022, Номер 23(10)

Опубликована: Авг. 24, 2022

The emergence of SARS-CoV-2 variants has exacerbated the COVID-19 global health crisis. Thus far, all carry mutations in spike glycoprotein, which is a critical determinant viral transmission being responsible for attachment, receptor engagement and membrane fusion, an important target immunity. Variants frequently bear truncations flexible loops N-terminal domain (NTD) spike; functional importance these modifications remained poorly characterised. We demonstrate that NTD deletions are efficient entry by Alpha Omicron this correlates with stability. Phylogenetic analysis reveals extensive loop length polymorphisms across sarbecoviruses, setting evolutionary precedent remodelling. Guided analyses, we variations length, alone, sufficient to modulate virus entry. propose act fine-tune may provide mechanism navigate complex selection landscape encompassing optimisation essential functionality, immune-driven antigenic variation ongoing adaptation new host.

Язык: Английский

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Receptor-Binding Domain (RBD) Antibodies Contribute More to SARS-CoV-2 Neutralization When Target Cells Express High Levels of ACE2

Viruses, Год журнала: 2022, Номер 14(9), С. 2061 - 2061

Опубликована: Сен. 16, 2022

Neutralization assays are experimental surrogates for the effectiveness of infection- or vaccine-elicited polyclonal antibodies and therapeutic monoclonal targeting SARS-CoV-2. However, measured neutralization can depend on details assay. Here, we systematically assess how ACE2 expression in target cells affects by to different spike epitopes lentivirus pseudovirus assays. For high ACE2-expressing cells, receptor-binding domain (RBD) account nearly all neutralizing activity human sera. lower regions outside RBD make a larger (although still modest) contribution serum neutralization. These serum-level results mirrored antibodies: N-terminal (NTD) that do not compete binding incompletely neutralize but completely with expression. Our show level is an important variable, emphasizes role subset RBD-directed antibodies.

Язык: Английский

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