Convergence of immune escape strategies highlights plasticity of SARS-CoV-2 spike DOI Creative Commons
Xiaodi Yu, Jarek Juraszek, Lucy Rutten

et al.

PLoS Pathogens, Journal Year: 2023, Volume and Issue: 19(5), P. e1011308 - e1011308

Published: May 1, 2023

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

Language: Английский

Characteristics and Functions of Infection-enhancing Antibodies to the N-terminal Domain of SARS-CoV-2 DOI Creative Commons
Ruth I. Connor, Mrunal Sakharkar,

Garrett Rappazzo

et al.

Pathogens and Immunity, Journal Year: 2024, Volume and Issue: 9(2), P. 1 - 24

Published: June 18, 2024

Background: Fcγ-receptor (FcγR)-independent enhancement of SARS-CoV-2 infection mediated by N-terminal domain (NTD)-binding monoclonal antibodies (mAbs) has been observed in vitro, but the functional significance these vivo is less clear. Methods: We characterized 1,213 spike (S)-binding mAbs derived from COVID-19 convalescent patients for binding specificity to S protein, VH germ-line usage, and affinity maturation. Infection a vesicular stomatitis virus (VSV)-SARS-CoV-2 pseudovirus (PV) assay was respiratory intestinal epithelial cell lines, against variants concern (VOC). Proteomic deconvolution serum antibody repertoire used determine attributes secreted NTD-binding mAbs. Results: identified 72/1213 (5.9%) that enhanced PV assay. The majority (68%) recognized NTD, were with mild severe disease, persisted at least 5 months post-infection. not lines diminished or lost VOC. 2 identified, first time, NTD-binding, infection-enhancing among circulating immunoglobulins directly isolated serum. Functional analysis demonstrated robust activation FcγRIIIa associated recombinant proteins. Conclusions: Functionally active NTD-specific arise frequently during natural can last as major clonotypes convalescence. These display include FcγR activation, may be selected mutations NTD

Language: Английский

Citations

3
Two sides of the same coin: the N-terminal and the receptor-binding domains of SARS-CoV-2 Spike DOI
Massimo Ciccozzi, Stefano Pascarella

Future Virology, Journal Year: 2023, Volume and Issue: 18(2), P. 75 - 78

Published: Feb. 1, 2023

Tweetable abstract The SARS-CoV-2 Spike receptor binding domain and N-terminal interact with each other in an intricate mechanism. Mutations modulate the interplay between host molecules. This editorial comments on intricacies of interactions.

Language: Английский

Citations

7
Adaptive advantage of deletion repair in the N-terminal domain of the SARS-CoV-2 spike protein in variants of concern DOI Creative Commons
Miguel Álvarez-Herrera, Paula Ruiz-Rodríguez, Beatriz Navarro-Domínguez

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 24, 2024

Abstract Mutations within the N-terminal domain (NTD) of spike (S) protein are critical for emergence successful SARS-CoV-2 viral lineages. The NTD has been repeatedly impacted by deletions, often exhibiting complex and dynamic patterns, such as recurrent disappearance deletions in dominant variants. This study investigates influence repair lineage-defining found BA.1 lineage (Omicron variant) on success. We performed comparative genomic analyses more than 10 million genomes from GISAID to decipher transmission success viruses lacking S:ΔH69/V70, S:ΔV143/Y145, or both. These findings were contrasted against a screening publicly available raw sequencing data, revealing substantial discrepancies between data repositories, suggesting that spurious deletion observations may result systematic artifacts. Specifically, events approximately an order magnitude less frequent read-run survey. Our results suggest rare, isolated with limited direct evolution transmission. Nevertheless, could facilitate fitness-enhancing mutations. To explore potential drivers we characterized phenotype markers surrogate vitro system. Repair S:ΔH69/V70 reduced infectivity, while simultaneous S:ΔV143/Y145 led lower fusogenicity. In contrast, individual enhanced both fusogenicity susceptibility neutralization sera vaccinated individuals. work underscores genotype-phenotype landscape SARS-CoV-2, which impacts biology, efficiency, immune escape potential, offering insights relevance public health, surveillance, adaptive mechanisms driving emerging

Language: Английский

Citations

2
Emergence of SARS-CoV-2 omicron variant JN.1 in Tamil Nadu, India - Clinical characteristics and novel mutations DOI Creative Commons

Sivaprakasam T. Selvavinayagam,

Sathish Sankar, Yean K. Yong

et al.

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: July 30, 2024

In December 2023, we observed a notable shift in the COVID-19 landscape, when JN.1 omicron emerged as predominant SARS-CoV-2 variant with 95% incidence. We characterized clinical profile, and genetic changes JN.1, an emerging of interest. Whole genome sequencing was performed on positive specimens, followed by sequence analysis. Mutations within spike protein sequences were analysed compared previously reported lineages sub-lineages, to identify potential impact unique mutations structure possible alterations functionality. Several dynamic identified herein. Molecular docking analysis showed binding affinity, key interacting residues wild-type mutated structures host cell receptors entry viz., ACE2, CD147, CD209L AXL. Our data provides insights emergence newer variants highlights necessity for robust sustained global genomic surveillance SARS-CoV-2.

Language: Английский

Citations

2
Convergence of immune escape strategies highlights plasticity of SARS-CoV-2 spike DOI Creative Commons
Xiaodi Yu, Jarek Juraszek, Lucy Rutten

et al.

PLoS Pathogens, Journal Year: 2023, Volume and Issue: 19(5), P. e1011308 - e1011308

Published: May 1, 2023

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

Language: Английский

Citations

6