Biology subjects

Lytras, S.

Publications and source records attributed to Lytras, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Poxvirus gene repertoires are shaped by expansion-biased birth-and-death dynamics and genome architectural constraints

Poxviruses (family Poxviridae) are DNA viruses with exceptionally large genomes containing hundreds of genes. Yet the evolutionary processes contributing to their numerous gene repertoires remain insufficiently understood. Here, we inferred ortholog groups of genes across 58 poxvirus genomes and comprehensively analyzed gene gain, gene duplication, gene loss, horizontal gene transfer, and synteny conservation. Across poxviruses, coding capacity scaled linearly with genome length. Gene repertoires evolved through birth-and-death dynamics but generally expanded because gene gain cumulatively exceeded gene loss and gained genes subsequently underwent further duplication. Gene gain and duplication were concentrated in the terminal regions of most poxvirus genomes. In viral lineages whose gene repertoires expanded extensively, terminal-region expansion was accompanied by further accumulation of duplicated genes within the otherwise conserved central genomic regions. The phylogenetic placement of the bird-infecting genus Avipoxvirus, together with evidence that several horizontally acquired genes originated from mammals, raises the possibility of a mammalian origin for Avipoxvirus. Altogether, our findings reveal that poxvirus gene repertoire evolution is shaped by expansion-biased birth-and-death dynamics and genome architectural constraints.

evolutionary biology↗

bioRxiv2026

Protein language models learn underlying mutation biases alongside fitness landscapes

Protein language models (PLMs) score the effects of amino acid replacements as pseudo-probabilities, which are widely utilised to map protein fitness landscapes. However, because their training data relies on natural amino acid sequences, these models conflate protein structural constraints with nucleotide mutation biases and codon accessibility. Using the rapid emergence of the divergent influenza A H3N2 K lineage as a stress test, we investigate how base PLMs (ESM-2 and ESM-C) versus fine-tuned versions of these models capture mutational processes. We systematically implement a parameter sweep to explicitly couple (or decouple) empirical nucleotide mutational supply from PLM-assessed amino acid substitution pseudo-probabilities across evolutionary forecasting tasks. We find that base PLMs implicitly learn generic nucleotide-level mutational constraints, an effect strongly amplified by virus-specific fine-tuning. Incorporating explicit mutational accessibility significantly improves the binary prediction of observed amino acid changes. Conversely, when predicting the final circulating frequency of variants that have already emerged, adding mutational supply degrades performance, confirming that selection dominates post-emergence dynamics. Additionally, we perform amino-acid-level epistatic scanning to investigate protein structural constraints in the context of genetic background. This indicates the improbable antigenic substitution I160K is dependent on co-occurring S144N and N158D mutations in the H3N2 K lineage. Ultimately, current PLM pseudo-probabilities are a composite metric that conflates protein structural fitness with historical biases in mutational supply. Explicitly decoupling these independent evolutionary processes optimises predictive accuracy for real-world pathogen forecasting and isolates pure protein fitness for synthetic design pipelines.

evolutionary biology↗

bioRxiv2026

Novel African Rhinolophus bat ACE2 sequences reveal the determinants of Afro-Eurasian sarbecovirus entry

Sarbecoviruses, including SARS-CoV and SARS-CoV-2, are frequently linked to Rhinolophus bats as their putative natural reservoirs. Angiotensin-converting enzyme 2 (ACE2), a host carboxypeptidase widely expressed in mammalian tissues, plays a critical role in sarbecovirus infection by serving as the cellular receptor for the viral spike (S) protein. Given recent human outbreaks and pandemics caused by members of sarbecoviruses, and the wide distribution of Rhinolophus bats, it is essential to maintain surveillance of these viruses while improving our understanding of their interactions with bat hosts, particularly the ACE2 receptor. However, while Rhinolophus bats from Asia have been relatively well studied, African Rhinolophus bats remain underrepresented and require further investigation. In this study, five Rhinolophus bat lung samples were obtained from Zambia, and ACE2 genes from these individuals were cloned and sequenced. We further evaluated the susceptibility of ACE2 variants to a panel of sarbecoviruses, revealing key residues that influence viral infectivity. ACE2 polymorphism was observed among Rhinolophus simulator individuals, revealing multiple ACE2 genotypes within the sampled population. However, R. simulator ACE2s did not permit infection by the clade 3 Afro-Eurasian sarbecoviruses tested in this study. Notably, RhGB01 and BM48-31 virus utilized only Rhinolophus blasii ACE2. Mutational analyses further suggested that ACE2 residues 31 and 41 play important roles in modulating spike-ACE2 interactions. This study reports 4 unique ACE2 sequences of R. simulator and R. blasii, and provides new insights into the molecular interactions between African Rhinolophus species ACE2s and the S protein of sarbecoviruses circulating in Africa and Europe. ImportanceAs putative natural reservoirs of sarbecoviruses, including SARS-CoV and SARS-CoV-2, Rhinolophus bats play a critical role in the emergence of zoonotic coronaviruses, making it essential to understand their interactions with these viruses for future pandemic preparedness. While Asian Rhinolophus bats have been relatively well studied, African species remain underrepresented, highlighting the need for further investigation. In this study, we cloned and sequenced ACE2 genes of five Rhinolophus bats collected in Zambia, Africa. We identified ACE2 polymorphism among Rhinolophus simulator individuals, although this variation was not associated with susceptibility to the clade 3 Afro-Eurasian sarbecoviruses examined. In addition, we identified key ACE2 residues that govern SARS-CoV-2 spike-ACE2 interactions and contribute to distinct infectivity patterns across species. These findings expand our understanding of the molecular determinants of sarbecovirus host range and support improved surveillance and risk assessment of emerging coronaviruses.

microbiology↗

bioRxiv2026

Host innate immune response profiling reveals hidden viral infections across diverse animal species

Virus discovery using RNA-seq data from wildlife and livestock offers a powerful strategy for identifying unknown pathogens with pandemic potential. However, conventional approaches rely on homology-based searches that have limited sensitivity for highly divergent viruses, are computationally intensive at scale, and cannot distinguish true infections from contamination. Viral infection induces interferon-stimulated genes (ISGs), key components of the frontline antiviral defense, and their expression serves as a robust indicator of viral infection. Here, we developed a host-response-based virus discovery framework that rapidly quantifies ISG expression and predicts viral infection status. Applying this framework to [~]210,000 RNA-seq data sets from diverse mammalian and avian species, we identified hidden viral infections across diverse hosts, including those caused by highly divergent viruses missed by a conventional approach. Our framework complements existing virus discovery strategies by adding host innate immune response context and enabling computationally efficient prescreening for scalable viral surveillance. HighlightsO_LIHost response-based virus discovery in wildlife and livestock RNA-seq data C_LIO_LIQuantify interferon-stimulated gene (ISG) expression and predict viral infection C_LIO_LIAnalysis of [~]210,000 RNA-seq data sets reveals hidden viral infections C_LIO_LIDetects highly divergent viruses and scalable viral surveillance through rapid prescreening C_LI

microbiology↗

bioRxiv2025

Genetic diversity in horseshoe bat ACE2 and sarbecovirus spike proteins mutually shape one another

Angiotensin-converting enzyme 2 (ACE2) serves as the entry receptor for a wide diversity of sarbecoviruses naturally harboured by horseshoe bats (genus Rhinolophus). Despite the extensive circulation of these viruses in many horseshoe bat species, the potential interactions between virus and receptor evolution remain poorly understood. We sampled individuals of the intermediate horseshoe bat (Rhinolophus affinis) across Vietnam and identified 15 genotypes of ACE2 proteins, 10 of which are previously unreported. Phylogenetic analysis and infectivity assays with a panel of 36 sarbecovirus spike proteins indicated that the R. affinis ACE2 phylogeny has geographic structuring and genotypes originating from different geographic regions exhibit distinct infectivity phenotypes. We detected site-specific positive selection on ACE2 site 24 with the associated substitutions largely affecting the receptors sarbecovirus infectivity profile. Together, our findings suggest that the R. affinis within-species ACE2 diversity has likely been shaped through selection by past sarbecovirus infection. Similarly on the virus end, we use mutagenesis assays and structural analysis through cryo-EM, to delineate the proximal evolution of the Ra22QT77 spike defined by specialization to the ACE2 genotypes of horseshoe bats found in and near southern Vietnam, where the virus was sampled. Our findings contribute to a better understanding of host-sarbecovirus co-evolution dynamics and provide valuable insights into the receptor usage determinants of these viruses. HighlightsO_LIWe identify a total of 15 ACE2 genotypes in R. affinis bats from Vietnam. C_LIO_LIACE2 intraspecific polymorphism is geographically separated and associated with distinct sarbecovirus infectivity. C_LIO_LISite 24 of R. affinis ACE2 experiences positive selection and controls susceptibility to sarbecoviruses. C_LIO_LIBat ACE2s and sarbecovirus spikes are bidirectionally shaped by each others evolution. C_LI

microbiology↗

bioRxiv2025

Structural and phenotypic plasticity of the RBD loop2 region is a key determinant for HKU5r-CoVs' emergence in mink

The emergence of novel coronaviruses from animal reservoirs continues to pose a significant zoonotic threat. Here, we investigate the evolutionary origins and virological properties of a recently reported mink-derived HKU5-related coronavirus (nvHKU5r-CoV). Phylogenetic and recombination analyses reveal that nvHKU5r-CoV originated from bat HKU5-like viruses circulating in southeastern China. We characterize the spike loop2 region as a critical determinant of ACE2 receptor specificity, directly interacting with the receptor, and show that the bat HKU5r-CoV with the closest loop2 sequence to nvHKU5r-CoV could already utilize mink ACE2. Using AlphaFold3, we predicted spike-ACE2 binding interfaces consistent with our experimental infectivity results. Targeted mutagenesis demonstrates that a single amino acid substitution (R548S) enables robust entry of nvHKU5r-CoV via human ACE2. We further show that this substitution can arise in vitro during hACE2-expressing cell infection with a replication-competent VSV system. Molecular dating suggests that nvHKU5r-CoV transmitted from bats to mink within the last decade, consistent with an expansion of mink fur farming in China. Overall, our findings highlight the zoonotic potential of these viruses and the molecular and structural determinants underlying it, while emphasizing fur farming as a major risk factor for how bat HKU5r-CoVs can transmit to farmed animals and ultimately humans.

microbiology↗

bioRxiv2025

Integrative modeling of seasonal influenza evolution via AI-powered antigenic cartography

Seasonal influenza viruses evade host immunity through rapid antigenic evolution. Antigenicity is assessed by serological assays and typically visualized as antigenic maps, which represent antigenic differences among virus strains. However, conventional maps cannot directly infer the antigenicity of unexamined variants from their genotypes. Here, we present PLANT, a protein language model that projects influenza A/H3N2 viruses onto an antigenic map using HA protein sequences. Using PLANT-based cartography, we show that (i) H3N2 antigenic evolution accelerates during periods of disrupted global circulation, (ii) antigenic novelty accounts for a substantial portion of viral fitness advantage, and (iii) vaccine strains are often antigenically distant from circulating viruses. We further propose a PLANT-based framework for selecting vaccine strains with improved antigenic match than the WHO-recommended strains. This study provides a statistical foundation for integrated modeling of viral genotype, antigenicity, and fitness, offering quantitative insights into seasonal influenza virus evolution and supporting rational vaccine design.

microbiology↗

bioRxiv2025

COVID-19 vaccination induces cross-neutralisation of sarbecoviruses related to SARS-CoV-2

Close relatives of SARS-CoV-1 and SARS-CoV-2 continue to circulate in wildlife, posing an ongoing threat of zoonotic spillover. While vaccination played a key role in controlling the COVID-19 pandemic, variants of concern (VOC) with immune evasive substitutions emerged on multiple occasions, causing widespread breakthrough infections. The combined threats of zoonosis and newly emerging VOCs, coupled with the potential for recombination, underscore the need to assess the breadth of existing vaccine-mediated protection. Here, we investigate a cohort of older individuals (median age 68.5 years) for the potential of cross-neutralisation against Omicron lineage VOC and animal sarbecoviruses induced by four COVID-19 vaccine doses. Despite the recent use of a bivalent mRNA vaccine dose (encoding spike from Wu-1 and omicron), we observed that neutralisation of Omicron lineage VOCs such as BA.1 and BA.2 were reduced compared to SARS-CoV-2 Wu-1, suggesting an imprinted immune response from pre-Omicron lineage viruses. Similarly, both SARS-CoV-1 and a SARS-CoV-1-related bat CoV were neutralised less efficiently than SARS-CoV-2 Wu-1. Unexpectedly, however, we observed that two animal SARS-CoV-2-related viruses, BANAL-20-52 (from bats) and a pangolin-CoV, were more sensitive to serum neutralising antibodies than SARS-CoV-2 Wu-1 itself. These surprising findings suggest that vaccine-mediated adaptive immunity may provide efficient cross-protection against certain animal sarbecoviruses.

microbiology↗

bioRxiv2025

Molecular basis of sarbecovirus evolution and receptor tropism in natural hosts, potential intermediate hosts, and humans

The spike protein of many sarbecoviruses binds to the angiotensin-converting enzyme 2 (ACE2) receptor and facilitates viral entry. The diversification of the sarbecovirus spike gene and the mammalian ACE2 gene suggests that sarbecoviruses and their hosts have co-evolved, and the genetic diversity in these genes affects the host tropism of sarbecoviruses. Better comprehending the evolutionary potential of sarbecoviruses can lead to preparedness for the next pandemic. However, the host tropism of sarbecoviruses is not fully understood. Here, we performed round-robin pseudovirus infection assays using 53 sarbecoviruses and ACE2s from 17 mammals to elucidate the ACE2 tropism of sarbecoviruses in natural hosts, potential intermediate hosts and humans. We determined the factors responsible for the ACE2 tropism of sarbecoviruses through structural, phylogenetic analyses, and infection experiments, revealing which substitutions can expand the host range of sarbecoviruses. These results highlight the mechanisms modulating host tropism throughout sarbecovirus evolution.

microbiology↗

bioRxiv2025

Inferring context-specific site variation with evotuned protein language models

Multiple sequence alignments (MSAs) have been traditionally used for making inferences about site-specific diversity in proteins. Recent advancements in the field of artificial intelligence have highlighted the potential of protein language models (pLMs) to capture similar protein properties. Unlike MSAs, pLMs can make inferences from single sequences, without the need for a set of aligned sequences. In this study, we introduce a novel, pLM-based metric, termed pLM entropy, to assess protein site conservation and variability. We test this metric using versions of two popular pLMs (ESM-2 and protT5) fine-tuned on the diversity of different Influenza A virus serotype hemagglutinin proteins. Our study demonstrates how our pLM entropy metric can capture which sites are more likely to change in a specific sequence context and how fine-tuning pLMs on a set of evolutionarily related proteins (evotuning) can improve the models understanding of the groups diversity.

evolutionary biology↗

bioRxiv2024

Viro3D: a comprehensive database of virus protein structure predictions

Viruses are intracellular parasites of organisms from all domains of life. They infect and cause disease in humans, animals and plants but also play crucial roles in the ecology of microbial communities. Tolerance to genetic change, high-mutation rates, adaptations to hosts and immune escape has driven high divergence of viral genes, hampering their functional annotation and phylogenetic inference. The protein structure is more conserved than sequence and can be used for searches of distant homologs and evolutionary analysis of divergent proteins. Structures of viral proteins are traditionally underrepresented in public databases, but recent advances in protein structure prediction allows us to address this issue. Combining two state-of-the-art approaches, AlphaFold2-ColabFold and ESMFold, we predicted models for 85,000 proteins from 4,400 human and animal viruses, expanding the structural coverage for viral proteins by 30 times compared to experimental structures. We also performed structural and network analyses of the models to demonstrate their utility for functional annotation and inference of distant phylogenetic relationships. Taking this approach, we examined the deep evolutionary history of viral class-I fusion glycoproteins, gaining insights on the origins of coronavirus spike protein. To enable further discoveries, we have created Viro3D (https://viro3d.cvr.gla.ac.uk/), a virus species-centred protein structure database. It allows users to search, browse and download protein models from a virus of interest and explore similar structures present in other virus species. This resource will facilitate fundamental molecular virology, investigation of virus evolution, and may enable structure-informed design of therapies and vaccines.

microbiology↗

bioRxiv2024

From a single sequence to evolutionary trajectories: protein language models capture the evolutionary potential of SARS-CoV-2 protein sequences

Protein language models (PLMs) capture features of protein three-dimensional structure from amino acid sequences alone, without requiring multiple sequence alignments (MSA). The concepts of grammar and semantics from natural language have the potential to capture functional properties of proteins. Here, we investigate how these representations enable assessment of variation due to mutation. Applied to SARS-CoV-2s spike protein using in silico deep mutational scanning (DMS) we demonstrate the PLM, ESM-2, has learned the sequence context within which variation occurs, capturing evolutionary constraint. This recapitulates what conventionally requires MSA data to predict. Unlike other state-of-the-art methods which require protein structures or multiple sequences for training, we show what can be accomplished using an unmodified pretrained PLM. We demonstrate that the grammaticality and semantic scores represent novel metrics. Applied to SARS-CoV-2 variants across the pandemic we show that ESM-2 representations encode the evolutionary history between variants, as well as the distinct nature of variants of concern upon their emergence, associated with shifts in receptor binding and antigenicity. PLM likelihoods can also identify epistatic interactions among sites in the protein. Our results here affirm that PLMs are broadly useful for variant-effect prediction, including unobserved changes, and can be applied to understand novel viral pathogens with the potential to be applied to any protein sequence, pathogen or otherwise.

bioinformatics↗

bioRxiv2024

Diversity and evolution of the human anellome

Anelloviruses are a group of small, circular, single-stranded DNA viruses that are found ubiquitously across mammalian hosts. Here, we explored a large number of publicly available human microbiome datasets and retrieved a total of 829 anellovirus genomes, substantially expanding the known diversity of these viruses. The majority of new genomes fall within the three major human anellovirus genera: Alphatorquevirus, Betatorquevirus and Gammatorquevirus, while we also present one new genome of the under-sampled Hetorquevirus genus. The phylogeny reconstructed from the conserved ORF1 gene reveals three additional, previously undescribed, human anellovirus clades. We performed recombination analysis and show evidence of extensive recombination across all human anelloviruses. Interestingly, more than 95% of the detected events are between members of the same clade and only 15 inter-clade recombination events were detected. The breakpoints of recombination cluster in hotspots at the ends and outside of the ORF1 gene, while a recombination coldspot was detected within the gene. Our analysis suggests that anellovirus evolution is governed by homologous recombination, however events between distant viruses or ones producing chimaeric ORF1s likely lead to non-viable recombinants. The large number of genomes further allowed us to examine how essential genomic features vary across anelloviruses. These include functional domains in the ORF1 protein and the nucleotide motif of the replication loop region, required for the viruses rolling-circle replication. A subset of the genomes assembled in both this and previous studies are completely lacking these essential elements, opening up the possibility that anellovirus intracellular populations contain defective virus genomes (DVGs). Overall, our study highlights key features of anellovirus genomics and evolution, a largely understudied group of viruses whose potential in virus-based therapeutics is recently being explored.

evolutionary biology↗

bioRxiv2024

A Protein Language Model for Exploring Viral Fitness Landscapes

Successively emerging SARS-CoV-2 variants lead to repeated epidemic surges through escalated spreading potential (i.e., fitness). Modeling genotype-fitness relationship enables us to pinpoint the mutations boosting viral fitness and flag high-risk variants immediately after their detection. Here, we introduce CoVFit, a protein language model able to predict the fitness of variants based solely on their spike protein sequences. CoVFit was trained with genotype-fitness data derived from viral genome surveillance and functional mutation data related to immune evasion. When limited to only data available before the emergence of XBB, CoVFit successfully predicted the higher fitness of the XBB lineage. Fully-trained CoVFit identified 549 fitness elevation events throughout SARS-CoV-2 evolution until late 2023. Furthermore, a CoVFit-based simulation was able to predict the higher fitness of JN.1 subvariants before their detection. Our study provides both insight into the SARS-CoV-2 fitness landscape and a novel tool potentially transforming viral genome surveillance.

microbiology↗

bioRxiv2024

Mapping glycoprotein structure reveals defining events in the evolution of the Flaviviridae

Viral glycoproteins drive membrane fusion in enveloped viruses and determine host range, tissue tropism and pathogenesis. Despite their importance, there is a fragmentary understanding of glycoproteins within the Flaviviridae; for many species the glycoproteins have not yet been identified, for others, such as the hepaciviruses, the molecular mechanisms of membrane fusion remain uncharacterised. Here, we combine comprehensive phylogenetic analyses with systematic protein structure prediction to survey glycoproteins across the entire Flaviviridae. We discover class-II fusion systems, homologous to the orthoflavivirus E glycoprotein, in most species, including highly-divergent jingmenviruses and large genome flaviviruses. However, the E1E2 glycoproteins of the hepaci-, pegi- and pestiviruses are structurally distinct, may represent a novel class of fusion mechanism, and are strictly associated with infection of vertebrate hosts. By mapping glycoprotein distribution onto the underlying phylogeny we reveal a complex history of evolutionary events that have shaped the diverse virology and ecology of the Flaviviridae.

microbiology↗

bioRxiv2023

A novel approach to exploring the dark genome and its application to mapping of the vertebrate virus 'fossil record'.

BackgroundGenomic regions that remain poorly understood, often referred to as the "dark genome," contain a variety of functionally relevant and biologically informative genome features. These include endogenous viral elements (EVEs) - virus-derived sequences that can dramatically impact host biology and serve as a virus "fossil record". In this study, we introduce a database-integrated genome screening (DIGS) approach to investigating the dark genome in silico, focusing on EVEs found within vertebrate genomes. ResultsUsing DIGS on 874 vertebrate species genomes, we uncovered approximately 1.1 million EVE sequences, with over 99% originating from endogenous retroviruses or transposable elements that contain EVE DNA. We show that the remaining 6038 sequences represent over a thousand distinct horizontal gene transfer events across ten virus families, including some that have not previously been reported as EVEs. We explore the genomic and phylogenetic characteristics of non-retroviral EVEs and determine their rates of acquisition during vertebrate evolution. Our study uncovers novel virus diversity, broadens knowledge of virus distribution among vertebrate hosts, and provides new insights into the ecology and evolution of vertebrate viruses. ConclusionsWe comprehensively catalogue and analyse EVEs within 874 vertebrate genomes, shedding light on the distribution, diversity and long-term evolution of viruses, and revealing their extensive impact on vertebrate genome evolution. Our results demonstrate the power of linking a relational database management system to a similarity search-based screening pipeline for in silico exploration of the dark genome.

genomics↗

bioRxiv2023

The recency and geographical origins of the bat viruses ancestral to SARS-CoV and SARS-CoV-2

The emergence of SARS-CoV in 2002 and SARS-CoV-2 in 2019 has led to increased sampling of related sarbecoviruses circulating primarily in horseshoe bats. These viruses undergo frequent recombination and exhibit spatial structuring across Asia. Employing recombination-aware phylogenetic inference on bat sarbecoviruses, we find that the closest-inferred bat virus ancestors of SARS-CoV and SARS-CoV-2 existed just [~]1-3 years prior to their emergence in humans. Phylogeographic analyses examining the movement of related sarbecoviruses demonstrate that they traveled at similar rates to their horseshoe bat hosts and have been circulating for thousands of years in Asia. The closest-inferred bat virus ancestor of SARS-CoV likely circulated in western China, and that of SARS-CoV-2 likely circulated in a region comprising southwest China and northern Laos, both a substantial distance from where they emerged. This distance and recency indicate that the direct ancestors of SARS-CoV and SARS-CoV-2 could not have reached their respective sites of emergence via the bat reservoir alone. Our recombination-aware dating and phylogeographic analyses reveal a more accurate inference of evolutionary history than performing only whole-genome or single gene analyses. These results can guide future sampling efforts and demonstrate that viral genomic fragments extremely closely related to SARS-CoV and SARS-CoV-2 were circulating in horseshoe bats, confirming their importance as the reservoir species for SARS viruses.

evolutionary biology↗

bioRxiv2022

Virological characteristics of the SARS-CoV-2 XBB variant derived from recombination of two Omicron subvariants

In late 2022, the SARS-CoV-2 Omicron subvariants have highly diversified, and XBB is spreading rapidly around the world. Our phylogenetic analyses suggested that XBB emerged by recombination of two co-circulating BA.2 lineages, BJ.1 and BM.1.1.1 (a progeny of BA.2.75), during the summer of 2022 around India. In vitro experiments revealed that XBB is the most profoundly resistant variant to BA.2/5 breakthrough infection sera ever and is more fusogenic than BA.2.75. Notably, the recombination breakpoint is located in the receptor-binding domain of spike, and each region of recombined spike conferred immune evasion and augmented fusogenicity to the XBB spike. Finally, the intrinsic pathogenicity of XBB in hamsters is comparable to or even lower than that of BA.2.75. Our multiscale investigation provided evidence suggesting that XBB is the first documented SARS-CoV-2 variant increasing its fitness through recombination rather than single mutations.

microbiology↗