Deep mutational scans of XBB.1.5 and BQ.1.1 reveal ongoing epistatic drift during SARS-CoV-2 evolution

PLoS Pathogens, Год журнала: 2023, Номер 19(12), С. e1011901 - e1011901

Опубликована: Дек. 29, 2023

Substitutions that fix between SARS-CoV-2 variants can transform the mutational landscape of future evolution via epistasis. For example, large epistatic shifts in effects caused by N501Y underlied original emergence Omicron, but whether such saltations continue to define ongoing remains unclear. We conducted deep scans measure impacts all single amino acid mutations and single-codon deletions spike receptor-binding domain (RBD) on ACE2-binding affinity protein expression recent Omicron BQ.1.1 XBB.1.5 variants, we compared patterns earlier viral strains have previously profiled. As with previous scans, find many are tolerated or even enhance binding ACE2 receptor. The tolerance sites deletion largely conforms mutation. Though RBD not yet been seen dominant lineages, observe including at positions exhibit indel variation across broader sarbecovirus emerging interest, most notably well-tolerated Δ483 BA.2.86. substitutions distinguish induced as dramatic perturbations N501Y, identify drift interaction R493Q reversions 453, 455, 456, F456L defines XBB.1.5-derived EG.5 lineage. Our results highlight due epistasis, which may direct into new regions sequence space.

Язык: Английский

Sarbecovirus RBD indels and specific residues dictating multi-species ACE2 adaptiveness

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Март 14, 2024

Sarbecoviruses exhibit varying abilities in using angiotensin-converting enzyme 2 (ACE2) receptor^1-3. However, a comprehensive understanding of their multi-species ACE2 adaptiveness and the underlying mechanism remains elusive, particularly for many sarbecoviruses with various receptor binding motif (RBM) insertions/deletions (indels)^4-11. Here, we analyzed RBM sequences from 268 categorized into four indel types. We extensively examined capability 14 representative derivatives orthologues 51 bats five non-bat mammals. revealed that most longer RBMs (type-I), present broad tropism, whereas viruses single deletions Region 1 (type-II) or (type-III) generally narrow typically favoring hosts’ ACE2. double region (type-IV) complete loss usage. Subsequent investigations unveiled both loop critical residues significantly impact tropism different ways. Additionally, fine mapping based on type-IV elucidated role several clade-specific residues, within outside RBM, restricting Lastly, hypothesized evolution sarbecovirus indels illustrated how length, disulfide, adaptive mutations shape adaptiveness. This study provides profound insights mechanisms governing usage spillover risks sarbecoviruses.

Язык: Английский

Delineating the functional activity of antibodies with cross-reactivity to SARS-CoV-2, SARS-CoV-1 and related sarbecoviruses

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Апрель 25, 2024

The recurring spillover of pathogenic coronaviruses and demonstrated capacity sarbecoviruses, such SARS-CoV-2, to rapidly evolve in humans underscores the need better understand immune responses this virus family. For purpose, we characterized functional breadth potency antibodies targeting receptor binding domain (RBD) spike glycoprotein that exhibited cross-reactivity against SARS-CoV-2 variants, SARS-CoV-1 sarbecoviruses from diverse clades animal origins with potential. One neutralizing antibody, C68.61, showed remarkable neutralization both variants viruses different sarbecovirus clades. which targets a conserved RBD class 5 epitope, did not select for escape or culture nor have predicted among circulating strains, suggesting epitope is functionally constrained. We identified 11 additional SARS-CoV-2/SARS-CoV-1 cross-reactive target more sequence 4 epitopes within show activity subset one antibody every single tested. A these Fc-mediated effector functions as potent impact infection outcome models. Thus, our study regions across may serve therapeutics pandemic preparedness well blueprints design immunogens capable eliciting cross-neutralizing responses.

Язык: Английский