Evolutionary remodelling of N‐terminal domain loops fine‐tunes <scp>SARS‐CoV</scp>‐2 spike

Cantoni, Diego; Murray, Matthew J; Kalemera, Mphatso D; Dicken, Samuel J; Stejskal, Lenka; Brown, Georgina; Lytras, Spyros; Coey, Jonathon D.; McKenna, James; Bridgett, Stephen; Simpson, David; Fairley, Derek; Thorne, Lucy; Reuschl, Ann-Kathrin; Forrest, Calum; Ganeshalingham, Maaroothen; Muir, Luke; Palor, Machaela; Jarvis, Lisa; Willett, Brian J.; Power, Ultan F.; McCoy, Laura E.; Jolly, Clare; Towers, Greg J.; Doores, Katie J.; Robertson, David L.; Shepherd, Adrian J.; Reeves, Matthew B.; Bamford, Connor; Grove, Joe

doi:10.15252/embr.202154322

Cited by 25 publications

(35 citation statements)

References 92 publications

(125 reference statements)

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“…For SARS-CoV-2 entry into airway cells, this site is preferentially cleaved by host serine proteases, such as TMPRSS2, but it can alternatively be cleaved by endolyosomal cathepsins 19 , 91 . A number of recent articles have suggested that variation in the NTD of SARS-CoV-2, particularly via remodelling of external loops through the acquisition of deletions or insertions, can allosterically influence both S1–S2 cleavage and S2′ cleavage, and therefore fusion 92 – 94 .…”

Section: The Fcs In Sars-cov-2 Variant Emergencementioning

confidence: 99%

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

et al. 2023

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

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Section: The Fcs In Sars-cov-2 Variant Emergencementioning

confidence: 99%

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

et al. 2023

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“…It has been previously shown that mutations at some sites of the signal peptide could abrogate virus neutralization by antibodies due to changes of the signal peptide cleavage site ( McCallum et al, 2021 ). Changes of lengths and sequences of NTD loops mediate Spike membrane fusion, cell entry and extracellular stability ( Cantoni et al, 2022 ; Qing et al, 2021 ). Loops N1 (positions 14–26), N3 and N5 contribute to NTD supersite of binding of neutralizing antibodies ( Cerutti et al, 2021 ; McCallum et al, 2021 ).…”

Section: Resultsmentioning

confidence: 99%

Coordinated evolution at amino acid sites of SARS-CoV-2 spike

Neverov

Fedonin

Popova

et al. 2023

eLife

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SARS-CoV-2 has adapted in a stepwise manner, with multiple beneficial mutations accumulating in a rapid succession at origins of VOCs, and the reasons for this are unclear. Here, we searched for coordinated evolution of amino acid sites in the spike protein of SARS-CoV-2. Specifically, we searched for concordantly evolving site pairs (CSPs) for which changes at one site were rapidly followed by changes at the other site in the same lineage. We detected 46 sites which formed 45 CSP. Sites in CSP were closer to each other in the protein structure than random pairs, indicating that concordant evolution has a functional basis. Notably, site pairs carrying lineage defining mutations of the four VOCs that circulated before May 2021 are enriched in CSPs. For the Alpha VOC, the enrichment is detected even if Alpha sequences are removed from analysis, indicating that VOC origin could have been facilitated by positive epistasis. Additionally, we detected nine discordantly evolving pairs of sites where mutations at one site unexpectedly rarely occurred on the background of a specific allele at another site, for example on the background of wild-type D at site 614 (four pairs) or derived Y at site 501 (three pairs). Our findings hint that positive epistasis between accumulating mutations could have delayed the assembly of advantageous combinations of mutations comprising at least some of the VOCs.

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“…The rapid global spread of SARS-CoV-2 leads to emergence of variants with either higher transmissibility or decreased recognition by protective immune response. The NTD undergoes rapid antigenic drift and accumulates a larger number of mutations and especially deletions [ 42 , 43 ]. In this study, we describe two spike variants, one from Peru and one from Brazil with typical point mutations in the RBD but extensive and rare deletions in the NTD ( Fig 1 ).…”

Section: Discussionmentioning

confidence: 99%

“…In the last three years, the NTD domain of the SARS-CoV-2 spike has been confirmed as a hotspot for deletions [ 42 , 43 ]). Within NTD, deletions are further clustered around a few sites: residues 69–70, 141–143, 156–159, and 242–245.…”

Section: Discussionmentioning

confidence: 99%

Convergence of immune escape strategies highlights plasticity of SARS-CoV-2 spike

Juraszek

Rutten

et al. 2023

PLoS Pathog

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The global spread of the SARS-CoV-2 virus has resulted in emergence of lineages which impact the effectiveness of immunotherapies and vaccines that are based on the early Wuhan isolate. All currently approved vaccines employ the spike protein S, as it is the target for neutralizing antibodies. Here we describe two SARS-CoV-2 isolates with unusually large deletions in the N-terminal domain (NTD) of the spike. Cryo-EM structural analysis shows that the deletions result in complete reshaping of the NTD supersite, an antigenically important region of the NTD. For both spike variants the remodeling of the NTD negatively affects binding of all tested NTD-specific antibodies in and outside of the NTD supersite. For one of the variants, we observed a P9L mediated shift of the signal peptide cleavage site resulting in the loss of a disulfide-bridge; a unique escape mechanism with high antigenic impact. Although the observed deletions and disulfide mutations are rare, similar modifications have become independently established in several other lineages, indicating a possibility to become more dominant in the future. The observed plasticity of the NTD foreshadows its broad potential for immune escape with the continued spread of SARS-CoV-2.

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

Cited by 25 publications

References 92 publications

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

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

Coordinated evolution at amino acid sites of SARS-CoV-2 spike

Convergence of immune escape strategies highlights plasticity of SARS-CoV-2 spike

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