Biology subjects

Brown, J. C.

Publications and source records attributed to Brown, J. C..

At least 19 recordsLinked to original sources

bioRxiv2026

Antiviral Sulfonated Polymersomes Inhibit Corona-, Influenza-, and Alphavirus

A broad-spectrum antiviral is required to enable rapid intervention against current, newly emerging and mutating viruses. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza A virus (IAV), Sindbis virus (SINV) and chikungunya virus (CHIKV) all engage negatively charged moieties on host cells, such as heparan sulfate (HS) and sialic acid, to facilitate attachment for entry and infection. We designed HS-mimetic nanoparticles in the form of polymer vesicles (polymersomes) by blending membrane-forming and sulfonated copolymers. These biocompatible polymersomes successfully inhibited host cell infection of HS-dependent SARS-CoV-2 and HS-independent IAV in vitro with sub-nanomolar potency. Multivalent interaction of several virus ligands with a single polymersome as quantified by fluorescence correlation spectroscopy likely contributes to their potency. The sulfonated polymersomes also functioned in vivo as demonstrated by a reduction in the spread of SINV, an alphavirus model for CHIKV, in zebrafish embryos, which led to a significantly increased survival. Hence, our polymersomes could form the basis for an urgently required multifunctional broad-spectrum antiviral nanomedicine.

bioengineering↗

bioRxiv2025

Evolutionary rewiring of host metabolism and interferon signalling by SARS-CoV-2 variants

SARS-CoV-2 variants differ in transmissibility and immune evasion, but their effects on host-cell metabolism and signalling remain less defined. Using integrated transcriptomic, phosphoproteomic, and amino acid profiling in primary nasal epithelial cells, we compared early and late host responses to pre-Omicron variants (Alpha, Beta), Delta, and Omicron subvariants (BA.1, BA.5). Pre-Omicron strains broadly suppressed antiviral interferon-stimulated gene expression and reprogrammed metabolism by reducing mitochondrial oxidative phosphorylation and {beta}-oxidation. Delta infection was associated with extensive transcriptional and metabolic remodelling, characterised by activation of stress- and growth-related kinases and selective retention of biosynthetic amino acids, consistent with a host response to stress and viral modulation of interferon-associated signalling. In contrast, Omicron infection elicited a more restrained response dominated by cytokine and survival pathways, with limited metabolic activation and interferon suppression. Together, these findings suggest SARS-CoV-2 has progressively evolved toward a strategy that maintains efficient upper-airway replication while minimising epithelial stress and inflammation.

systems biology↗

bioRxiv2025

Identification of short peptides that correlate with cytoplasmic retention of human proteins

One group of human proteins found in the cytoplasm, but not in the nucleus is characterized by the presence of short (6-9aa), specific amino acid sequences thought to be involved in retaining proteins in the cytoplasm (cytoplasmic retention sequences). While strong evidence supports the ability of some peptides to act in this way, the number of such supported cases is small. We have taken the view that the situation would be improved by enhancing the methods available to identify cytoplasmic retention (CR) peptides. Here we describe an appropriate bioinformatic method to identify CR peptides using information about their location at the ends of cytoplasmic proteins. The method was then used to link seven different human cytoplasmic proteins with peptides suggested to have cytoplasmic retention activity. Further analysis was carried out with isoforms of the cytoplasmic proteins identified. Amino acid sequence information showed that while the proposed CR amino acid sequences can be the same or distinct in different protein isoforms, they are always located at the same site in the protein. For instance, while the proposed retention sequence of CCDC57 isoform X18 is MLARLVSNS, in isoform 7 it is SEPALNEL yet the two sequences are each located between amino acids 5 and 13 in the CCDC57 sequence. The results support the view that protein isoform is involved in determining the location of the CR sequence in a protein while the peptide sequence itself affects other variables such as the sub-region of the cytoplasm the protein needs to occupy. Overall, the study yielded identification of 15 candidate CR peptides in which 10 of the 15 have un-related amino acid sequences.

cell biology↗

bioRxiv2024

Connectivity between supplementary motor complex and primary motor cortex: a dual-coil paired-pulse TMS study

In recent years, dual-coil paired-pulse transcranial magnetic stimulation (ppTMS) has garnered interest for its potential in elucidating neural circuit dynamics. In this study, the dual-coil ppTMS was utilized to assess the effective connectivity between the supplementary motor complex (SMC) and the primary motor cortex (M1) in humans. A robust facilitatory connection between the SMC and M1 was observed, manifested as a 19% increase in mean peak-to-peak motor-evoked potentials following preconditioning of SMC 7 ms prior to M1 stimulation. Importantly, the facilitatory influence of SMC only occurred when the preconditioning stimulation was administered 4 cm anterior to Cz but not when applied at 5-cm, 6-cm, or 7-cm distance. While previous work has focused on demonstrating important temporal dynamics for SMC-M1 plasticity, the present findings highlight a critical contribution of spatial specificity for modulation of SMC-M1 circuitry. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/610643v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@12fb447org.highwire.dtl.DTLVardef@e4bfacorg.highwire.dtl.DTLVardef@1e3d262org.highwire.dtl.DTLVardef@93984_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIThe conditioned stimulus induced larger MEPs compared to the unconditioned stimulus C_LIO_LIThe connectivity between SMC and M1 diminished when the SMC coil was moved forward C_LIO_LIFindings highlight the importance of spatial specificity for modulation of SMC-M1 circuitry C_LI

neuroscience↗

bioRxiv2024

A cup of coffee can boost your motor performance: Enhanced motor sequence learning with caffeine

Caffeine is consumed in various beverages, such as coffee, energy drinks, soda, and tea. The effects of caffeine have been shown to manifest in various ways across different studies. Some studies suggest that caffeine can enhance motor performance. Despite this, numerous motor learning studies do not control for participants caffeine intake or do not record whether participants consumed caffeine. The purpose of this study was to compare the motor learning performance (i.e., online improvement) of individuals who consumed caffeine and those who did not before practice with a novel motor sequence task. Sixty-five right-handed healthy undergraduate students participated in this study. Individuals reported their caffeine consumption through a pre-experiment questionnaire prior to performing an eight-item serial reaction time task. The participants who consumed caffeine reported drinking one cup of coffee on average 158.8 minutes before performing the sequential task. The motor performance of individuals who consumed caffeine was compared to those who did not, with the caffeine-consuming group (n = 13) exhibiting faster response times during online learning than the non-caffeine group (n = 52). The findings of this study suggest that caffeine should be controlled for in future motor learning research.

neuroscience↗

bioRxiv2024

Combined effects of pharmacological interventions and intermittent theta-burst stimulation on motor sequence learning

Drugs that modulate N-methyl-D-aspartate (NMDA) or {gamma}-Aminobutyric acid type A (GABAA) receptors can shed light on their role in synaptic plasticity mechanisms underlying the effects of non-invasive brain stimulation. However, research on the combined effects of these drugs and exogenous stimulation on motor learning is limited. This study aimed to investigate the effects of pharmacological interventions combined with intermittent theta-burst stimulation (iTBS) on human motor learning. Nine right-handed healthy subjects (mean age {+/-} SD: 31.56 {+/-} 12.96 years; 6 females) participated in this double-blind crossover study. All participants were assigned to four drug conditions in a randomized order: (1) D-cycloserine (partial NMDA receptor agonist), (2) D-cycloserine + dextromethorphan (NMDA receptor agonist + antagonist), (3) lorazepam (GABAA receptor agonist), and (4) placebo (identical microcrystalline cellulose capsule). After drug intake, participants practiced the 12-item keyboard sequential task as a baseline measure. Two hours after drug intake, iTBS was administered at the primary motor cortex. Following iTBS, the retention test was performed in the same manner as the baseline measure. Our findings revealed that lorazepam combined with iTBS impaired motor learning during the retention test. Future studies are still needed for a better understanding of the mechanisms through which TMS may influence human motor learning.

neuroscience↗

bioRxiv2023

Virion morphology and on-virus spike protein structures of diverse SARS-CoV-2 variants

The evolution of SARS-CoV-2 variants with increased fitness has been accompanied by structural changes in the spike (S) proteins that are the major target for the adaptive immune response. Single-particle cryo-EM analysis of soluble S from SARS-CoV-2 variants has revealed this structural adaptation at high-resolution. The analysis of S trimers in situ on intact virions has the potential to provide more functionally relevant insights into S structure and virion morphology. Here, we characterized B.1, Alpha, Beta, Gamma, Delta, Kappa, and Mu variants by cryo-electron microscopy and tomography, assessing S cleavage, virion morphology, S incorporation, "in-situ" high-resolution S structures and the range of S conformational states. We found no evidence for adaptive changes in virion morphology, but describe multiple different positions in the S protein where amino acid changes alter local protein structure. Considered together, our data is consistent with a model where amino acid changes at multiple positions from the top to the base of the spike cause structural changes that can modulate the conformational dynamics of S.

microbiology↗

bioRxiv2023

Novel conserved human DNA sequence supports expression of long genes

The study described here was carried out to pursue the idea that a truncated, transposition incompetent fragment of a LINE1 retrotransposon may affect the expression of a human gene when it is located inside the gene sequence. NCBI BLAST was used to probe the human genome to identify protein coding genes containing an abundant [~]1500bp LINE1 fragment (called t1519) in the gene body. The length and expression level of such genes was then compared with the same properties in genes that lack t1519 in human chromosomes 16-18. The results showed a striking effect of t1519 on long genes, those with lengths greater than [~]140 kb. Nearly all were found to have one or more t1519 sequences in the coding region. In contrast, genes in the common length range (less than 140 kb) could either have t1519 or not. A correlation was also observed with the level of gene expression. While expression of long, t1519-containing genes was limited to [~]50 TPM, genes in the common length range could be much higher, in the range of 500-600 TPM, regardless of whether or not they have t1519 elements. Contrasting results were obtained when the analysis was performed with lncRNAs rather than with protein-coding genes. Among lncRNA genes a chromosome-specific effect was observed. Restricted expression correlating with the presence of t1519 was observed in both long and common length genes of chromosomes 16 and 17, but not in chromosome 18. The results are interpreted to support a strong suppressive effect of t1519 on expression of long protein coding genes and on both long and common length lncRNA genes of chromosomes 16 and 17. It is suggested that the suppressive effect on expression, particularly among long genes, meets a need for the cell to limit the overall level of transcription it can support. Author summaryAlthough LINE1 DNA sequence elements are well known for their ability to replicate and move autonomously within the human genome, these features are observed in only a small proportion (0.02%) of the total human LINE1 population. Nearly all of the total [~]500,000 LINE1 elements are fragments of full-length LINE1 and are inactive for autonomous replication or movement. Truncated, inactive LINE1 sequences are found throughout the human genome including within the body of protein-coding genes, and this intragenic population is the subject of the study described here. The goal was to extend what is known about the properties of intragenic LINE1 sequences. The study was carried out with t1519, a truncated LINE1 sequence composed of the 3 terminal [~]1500 bp of the [~]6000 bp full length LINE1 element, and with the sequences of three human chromosomes 16, 17 and 18, that are rich in t1519 sequences. NCBI BLAST was used to identify t1519-containing genes in each chromosome, and the length and expression level of those genes was compared with control genes lacking t1519. A striking result was observed in the case of long protein-coding genes, genes longer than 140 kb. Nearly all had one or more t1519 sequences in the gene body, all in introns. An effect on the level of gene expression was also observed. Low expression (<50 TPM) was found in all long, t1519 positive genes while much higher levels (500-600 TPM) were found with genes in the common length range (< 140 kb) regardless of the presence of t1519. Similar results were obtained when lncRNA genes were studied instead of protein-coding ones. The results are interpreted to support a strong suppressive effect of t1519 on expression of long protein coding genes and also on certain lncRNA genes. It is suggested that the suppressive effect is due to a need for the cell to limit the overall level of transcription it can support.

genomics↗

bioRxiv2023

Lysine 36 of Drosophila histone H3.3 supports adult longevity

Aging is a multifactorial process that disturbs homeostasis, increases disease susceptibility, and ultimately results in death. Although the definitive set of molecular mechanisms responsible for aging remain to be discovered, epigenetic change over time is proving to be a promising piece of the puzzle. Several posttranslational histone modifications (PTMs) have been linked to the maintenance of longevity. Here, we focus on lysine-36 of the replication-independent histone protein, H3.3 (H3.3K36). To interrogate the role of this residue in Drosophila developmental gene regulation, we generated a lysine to arginine mutant that blocks the activity of its cognate modifying enzymes. We found that an H3.3BK36R mutation causes a significant reduction in adult lifespan, accompanied by dysregulation of the genomic and transcriptomic architecture. Transgenic co-expression of wild-type H3.3B completely rescues the longevity defect. Because H3.3 is known to accumulate in non-dividing tissues, we carried out transcriptome profiling of young vs aged adult fly heads. The data show that loss of H3.3K36 results in age-dependent misexpression of NF-{kappa}B and other innate immune target genes, as well as defects in silencing of heterochromatin. We propose H3.3K36 maintains the postmitotic epigenomic landscape, supporting longevity by regulating both pericentric and telomeric retrotransposons and by suppressing aberrant immune signaling.

genetics↗

bioRxiv2023

Restoring adiponectin via rosiglitazone ameliorates tissue wasting in mice with lung cancer.

The cancer associated cachexia syndrome (CACS) is a systemic metabolic disorder resulting in loss of body weight due to skeletal muscle and adipose tissues atrophy. CACS is particularly prominent in lung cancer patients, where it contributes to poor quality of life and excess mortality. Using the Kras/Lkb1 (KL) mouse model, we found that CACS is associated with white adipose tissue (WAT) dysfunction that directly affects skeletal muscle homeostasis. WAT transcriptomes showed evidence of reduced adipogenesis, and, in agreement, we found low levels of circulating adiponectin. To preserve adipogenesis and restore adiponectin levels, we treated mice with the PPAR-{gamma} agonist, rosiglitazone. Rosiglitazone treatment increased serum adiponectin levels, delayed weight loss, and preserved skeletal muscle and adipose tissue mass, as compared to vehicle-treated mice. The preservation of muscle mass with rosiglitazone was associated with increases in AMPK and AKT activity. Similarly, activation of the adiponectin receptors in muscle cells increased AMPK activity, anabolic signaling, and protein synthesis. Our data suggest that PPAR-{gamma} agonists may be a useful adjuvant therapy to preserve tissue mass in lung cancer. Key points- The PPAR-{gamma} agonist, rosiglitazone, restores circulating adiponectin levels in mice with lung cancer. - Rosiglitazone preserves skeletal muscle and adipose tissue mass in mice with lung cancer. - The preservation of muscle mass with rosiglitazone is associated with increases in AMPK and AKT activity. - Stimulation of adiponectin signaling increases AMPK activity, anabolic signaling, and protein synthesis in muscle cell culture.

cancer biology↗

bioRxiv2023

Phenotyping the virulence of SARS-CoV-2 variants in hamsters by digital pathology and machine learning

SARS-CoV-2 has continued to evolve throughout the COVID-19 pandemic, giving rise to multiple variants of concern (VOCs) with different biological properties. As the pandemic progresses, it will be essential to test in near real time the potential of any new emerging variant to cause severe disease. BA.1 (Omicron) was shown to be attenuated compared to the previous VOCs like Delta, but it is possible that newly emerging variants may regain a virulent phenotype. Hamsters have been proven to be an exceedingly good model for SARS-CoV-2 pathogenesis. Here, we aimed to develop robust quantitative pipelines to assess the virulence of SARS-CoV-2 variants in hamsters. We used various approaches including RNAseq, RNA in situ hybridization, immunohistochemistry, and digital pathology, including software assisted whole section imaging and downstream automatic analyses enhanced by machine learning, to develop methods to assess and quantify virus-induced pulmonary lesions in an unbiased manner. Initially, we used Delta and Omicron to develop our experimental pipelines. We then assessed the virulence of recent Omicron sub-lineages including BA.5, XBB, BQ.1.18, BA.2 and BA.2.75. We show that in experimentally infected hamsters, accurate quantification of alveolar epithelial hyperplasia and macrophage infiltrates represent robust markers for assessing the extent of virus-induced pulmonary pathology, and hence virus virulence. In addition, using these pipelines, we could reveal how some Omicron sub-lineages (e.g., BA.2.75) have regained virulence compared to the original BA.1. Finally, to maximise the utility of the digital pathology pipelines reported in our study, we developed an online repository containing representative whole organ histopathology sections that can be visualised at variable magnifications (https://covid-atlas.cvr.gla.ac.uk). Overall, this pipeline can provide unbiased and invaluable data for rapidly assessing newly emerging variants and their potential to cause severe disease.

microbiology↗

bioRxiv2023

Modelling the viral dynamics of the SARS-CoV-2 Delta and Omicron variants in different cell types

We use viral kinetic models fitted to viral load data from in vitro studies to explain why the SARS-CoV-2 Omicron variant replicates faster than the Delta variant in nasal cells, but slower than Delta in lung cells, which could explain Omicrons higher transmission potential and lower severity. We find that in both nasal and lung cells, viral infectivity is higher for Omicron but the virus production rate is higher for Delta. However, the differences are unequal between cell types, and ultimately leads to the basic reproduction number and growth rate being higher for Omicron in nasal cells, and higher for Delta in lung cells. In nasal cells, Omicron alone can enter via a TMPRSS2-independent pathway, but it is primarily increased efficiency of TMPRSS2-dependent entry which accounts for Omicrons increased activity. This work paves the way for using within-host mathematical models to understand the transmission potential and severity of future variants.

microbiology↗

bioRxiv2023

Propylene glycol inactivates respiratory viruses and prevents airborne transmission

Viruses are vulnerable as they transmit between hosts and we aimed to exploit this critical window. We found that the ubiquitous, safe, inexpensive and biodegradable small molecule propylene glycol (PG) has robust virucidal activity. Propylene glycol rapidly inactivates influenza, SARS-CoV-2 and a broad range of other enveloped viruses, and reduces disease burden in mice when administered intranasally at concentrations commonly found in nasal sprays. Most critically, aerosolized PG efficiently abolishes influenza and SARS-CoV-2 infectivity within airborne droplets, potently preventing infection at levels significantly below those well-tolerated by mammals. We present PG vapor as a first-in-class non-toxic airborne virucide, to prevent transmission of existing and emergent viral pathogens, with clear and immediate implications for public health. One-sentence summaryPropylene glycol is a potent and safe virucidal compound that could be used to limit and control infections.

microbiology↗

bioRxiv2023

Backup transcription factor binding sites protect human genes from mutations in the promoter

This study was designed to test the idea that human gene promoters have evolved to be resistant to the effects of mutations in their primary function, the control of gene expression. It is proposed that the transcription factor/transcription factor binding site (TF/TFBS) pair having the greatest effect on control of a gene is the one with the highest abundance in the promoter. Other pairs would have the same effect on gene expression and would predominate in the event of a mutation in the most abundant pair. It is expected that the overall promoter architecture proposed here will be highly resistant to mutagenic change that would otherwise affect expression of the gene. The idea was tested beginning with a database of 42 human genes highly specific for expression in brain. For each gene, information was accumulated about its expression level and about the TFBS occupancy of the five most abundant TF/TFBS pairs. Expression level was then plotted against TFBS occupancy separately for each of the five pairs, and the plots were compared with each other. The plots were found to be similar, and the results were interpreted to indicate that the TFBS occupancy ranks evolved to yield the same effect on gene expression level with multiple ranks able to function in the event of mutation in another. A similar analysis was conducted with a database of 31 human liver specific genes, and the overall result was found to be the same. Backup TFBS occupancy ranks were interpreted to be present in both brain and liver specific genes. Finally, the TFBSs in the brain specific and liver specific gene populations were compared with each other with the goal of identifying any brain selective or liver selective TFBSs. Of the 89 TFBSs in the pooled population, 58 were found only in brain specific but not liver specific genes, 8 only in liver specific but not brain specific genes and 23 were found in both brain and liver specific genes. The results were interpreted to emphasize the large number of TFBS in brain specific but not liver specific genes.

molecular biology↗

bioRxiv2022

Distinct roles for canonical and variant histone H3 lysine 36 in Polycomb silencing

Polycomb complexes regulate cell-type specific gene expression programs through heritable silencing of target genes. Trimethylation of histone H3 lysine 27 (H3K27me3) is essential for this process. Perturbation of H3K36 is thought to interfere with H3K27me3. We show that mutants of Drosophila replication-dependent (H3.2K36R) or -independent (H3.3K36R) histone H3 genes generally maintain Polycomb silencing and reach later stages of development. In contrast, combined (H3.3K36RH3.2K36R) mutants display widespread Hox gene misexpression and fail to develop past the first larval stage. Chromatin profiling revealed that the H3.2K36R mutation disrupts H3K27me3 levels broadly throughout silenced domains, whereas these regions are mostly unaffected in H3.3K36R animals. Analysis of H3.3 distributions showed that this histone is enriched at presumptive PREs (Polycomb Response Elements) located outside of silenced domains but relatively depleted from those inside. We conclude that H3.2 and H3.3 K36 residues collaborate to repress Hox genes using different mechanisms. Short summaryHistone H3.2 and H3.3 K36 residues ensure Hox gene silencing and enable development by different, but synergistic mechanisms.

genomics↗

bioRxiv2022

Omicron breakthrough infections in vaccinated or previously infected hamsters

The second and third years of the SARS-CoV-2 pandemic have been marked by the repeated emergence and replacement of variants with genetic and phenotypic distance from the ancestral strains, the most recent examples being Delta and Omicron. Here we describe a hamster contact exposure challenge model to assess protection conferred by vaccination or prior infection against re-infection. We found that 2-doses of self-amplifying RNA vaccine based on the ancestral spike ameliorated weight loss following Delta infection and decreased viral loads, but had minimal effect on Omicron/BA.1 infection. Prior infection with ancestral or Alpha variant was partially protective against Omicron/BA.1 infection, whereas all animals previously infected with Delta and exposed to Omicron became infected, although shed less virus. We further tested whether prior infection with Omicron/BA.1 protected from re-infection with Delta or Omicron/BA.2. Omicron/BA.1 was protective against Omicron/BA.2, but not Delta reinfection, again showing Delta and Omicron have a very large antigenic distance. Indeed, cross-neutralisation assays with human antisera from otherwise immunonaive individuals (unvaccinated and no known prior infection), confirmed a large antigenic distance between Delta and Omicron. Prior vaccination followed by Omicron or Delta breakthrough infection led to a higher degree of cross-reactivity to all tested variants. To conclude, cohorts whose only immune experience of COVID is Omicron/BA.1 infection may be particularly vulnerable to future circulation of Delta or Delta-like derivatives. In contrast, repeated exposure to antigenically distinct spikes, via infection and or vaccination drives a more cross-reactive immune response, both in hamsters and people. One Sentence SummaryInfection with the Delta and Omicron SARS-CoV-2 variants do not provide cross-protective immunity against reinfection with one another in hamsters.

microbiology↗

bioRxiv2022

The SARS-CoV-2 variant, Omicron, shows rapid replication in human primary nasal epithelial cultures and efficiently uses the endosomal route of entry.

The SARS-CoV-2 Omicron/BA.1 lineage emerged in late 2021 and rapidly displaced the Delta variant before being overtaken itself globally by, the Omicron/BA.2 lineage in early 2022. Here, we describe how Omicron BA.1 and BA.2 show a lower severity phenotype in a hamster model of pathogenicity which maps specifically to the spike gene. We further show that Omicron is attenuated in a lung cell line but replicates more rapidly, albeit to lower peak titres, in human primary nasal cells. This replication phenotype also maps to the spike gene. Omicron spike (including the emerging Omicron lineage BA.4) shows attenuated fusogenicity and a preference for cell entry via the endosomal route. We map the altered Omicron spike entry route and partially map the lower fusogenicity to the S2 domain, particularly the substitution N969K. Finally, we show that pseudovirus with Omicron spike, engineered in the S2 domain to confer a more Delta-like cell entry route retains the antigenic properties of Omicron. This shows a distinct separation between the genetic determinants of these two key Omicron phenotypes, raising the concerning possibility that future variants with large antigenic distance from currently circulating and vaccine strains will not necessarily display the lower intrinsic severity seen during Omicron infection.

microbiology↗

bioRxiv2021

SARS-CoV-2 Omicron-B.1.1.529 Variant leads to less severe disease than Pango B and Delta variants strains in a mouse model of severe COVID-19

COVID-19 is a spectrum of clinical symptoms in humans caused by infection with SARS-CoV-2. The B.1.1.529 Omicron variant is rapidly emerging and has been designated a Variant of Concern (VOC). The variant is highly transmissible and partially or fully evades a spectrum of neutralising antibodies due to a high number of substitutions in the spike glycoprotein. A major question is the relative severity of disease caused by the Omicron variant compared with previous and currently circulating variants of SARS-CoV-2. To address this, a mouse model of infection that recapitulates severe disease in humans, K18-hACE2 mice, were infected with either a Pango B, Delta or Omicron variant of SARS-CoV-2 and their relative pathogenesis compared. In contrast to mice infected with Pango B and Delta variant viruses, those infected with the Omicron variant had less severe clinical signs (weight loss), showed recovery and had a lower virus load in both the lower and upper respiratory tract. This is also reflected by less extensive inflammatory processes in the lungs. Although T cell epitopes may be conserved, the antigenic diversity of Omicron from previous variants would suggest that a change in vaccine may be required to mitigate against the higher transmissibility and global disease burden. However, the lead time to develop such a response may be too late to mitigate the spread and effects of Omicron. These animal model data suggest the clinical consequences of infection with the Omicron variant may be less severe but the higher transmissibility could still place huge burden upon healthcare systems even if a lower proportion of infected patients are hospitalised.

microbiology↗