In middle to late 2023, a sublineage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron XBB, EG.5.1 (a progeny of XBB.1.9.2), is spreading rapidly around the world. We performed multiscale investigations, including phylogenetic analysis, epidemic dynamics modeling, infection experiments using pseudoviruses, clinical isolates, and recombinant viruses in cell cultures and experimental animals, and the use of human sera and antiviral compounds, to reveal the virological features of the newly emerging EG.5.1 variant. Our phylogenetic analysis and epidemic dynamics modeling suggested that two hallmark substitutions of EG.5.1, S:F456L and ORF9b:I5T are critical to its increased viral fitness. Experimental investigations on the growth kinetics, sensitivity to clinically available antivirals, fusogenicity, and pathogenicity of EG.5.1 suggested that the virological features of EG.5.1 are comparable to those of XBB.1.5. However, cryo-electron microscopy revealed structural differences between the spike proteins of EG.5.1 and XBB.1.5. We further assessed the impact of ORF9b:I5T on viral features, but it was almost negligible in our experimental setup. Our multiscale investigations provide knowledge for understanding the evolutionary traits of newly emerging pathogenic viruses, including EG.5.1, in the human population.

• Klíčová slova
• COVID‐19, EG.5.1, ORF9b, Omicron, SARS‐CoV‐2, pathogenicity,
• MeSH
• antivirové látky farmakologie   MeSH
• Cercopithecus aethiops MeSH
• COVID-19 * virologie   MeSH
• elektronová kryomikroskopie MeSH
• fylogeneze * MeSH
• glykoprotein S, koronavirus * genetika   chemie   MeSH
• lidé MeSH
• myši MeSH
• SARS-CoV-2 * genetika   MeSH
• Vero buňky MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antivirové látky MeSH
• glykoprotein S, koronavirus * MeSH
• spike protein, SARS-CoV-2 MeSH Prohlížeč

Most studies investigating the characteristics of emerging SARS-CoV-2 variants have been focusing on mutations in the spike proteins that affect viral infectivity, fusogenicity, and pathogenicity. However, few studies have addressed how naturally occurring mutations in the non-spike regions of the SARS-CoV-2 genome impact virological properties. In this study, we proved that multiple SARS-CoV-2 Omicron BA.2 mutations, one in the spike protein and another downstream of the spike gene, orchestrally characterize this variant, shedding light on the importance of Omicron BA.2 mutations out of the spike protein.

• Klíčová slova
• BA.1, BA.2, COVID-19, Omicron, SARS-CoV-2, fusogenicity, growth capacity, immune resistance, pathogenicity,
• MeSH
• COVID-19 virologie   MeSH
• genom virový * genetika   MeSH
• glykoprotein S, koronavirus * genetika   MeSH
• lidé MeSH
• mutace * MeSH
• SARS-CoV-2 * genetika   patogenita   fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• glykoprotein S, koronavirus * MeSH
• spike protein, SARS-CoV-2 MeSH Prohlížeč

In late 2022, SARS-CoV-2 Omicron subvariants have become highly diversified, and XBB is spreading rapidly around the world. Our phylogenetic analyses suggested that XBB emerged through the recombination of two cocirculating BA.2 lineages, BJ.1 and BM.1.1.1 (a progeny of BA.2.75), during the summer of 2022. XBB.1 is the variant most profoundly resistant to BA.2/5 breakthrough infection sera to date and is more fusogenic than BA.2.75. The recombination breakpoint is located in the receptor-binding domain of spike, and each region of the recombinant spike confers immune evasion and increases fusogenicity. We further provide the structural basis for the interaction between XBB.1 spike and human ACE2. Finally, the intrinsic pathogenicity of XBB.1 in male hamsters is comparable to or even lower than that of BA.2.75. Our multiscale investigation provides evidence suggesting that XBB is the first observed SARS-CoV-2 variant to increase its fitness through recombination rather than substitutions.

• MeSH
• COVID-19 * MeSH
• fylogeneze MeSH
• glykoprotein S, koronavirus genetika   MeSH
• křečci praví MeSH
• lidé MeSH
• rekombinace genetická MeSH
• SARS-CoV-2 genetika   MeSH
• zvířata MeSH
• Check Tag
• křečci praví MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• glykoprotein S, koronavirus MeSH
• spike protein, SARS-CoV-2 MeSH Prohlížeč

In late 2022, various Omicron subvariants emerged and cocirculated worldwide. These variants convergently acquired amino acid substitutions at critical residues in the spike protein, including residues R346, K444, L452, N460, and F486. Here, we characterize the convergent evolution of Omicron subvariants and the properties of one recent lineage of concern, BQ.1.1. Our phylogenetic analysis suggests that these five substitutions are recurrently acquired, particularly in younger Omicron lineages. Epidemic dynamics modelling suggests that the five substitutions increase viral fitness, and a large proportion of the fitness variation within Omicron lineages can be explained by these substitutions. Compared to BA.5, BQ.1.1 evades breakthrough BA.2 and BA.5 infection sera more efficiently, as demonstrated by neutralization assays. The pathogenicity of BQ.1.1 in hamsters is lower than that of BA.5. Our multiscale investigations illuminate the evolutionary rules governing the convergent evolution for known Omicron lineages as of 2022.

• MeSH
• biotest MeSH
• COVID-19 * MeSH
• fylogeneze MeSH
• křečci praví MeSH
• neutralizující protilátky MeSH
• protilátky virové MeSH
• SARS-CoV-2 genetika   MeSH
• substituce aminokyselin MeSH
• zvířata MeSH
• Check Tag
• křečci praví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• neutralizující protilátky MeSH
• protilátky virové MeSH