Biology subjects

Lewis, C. B.

Publications and source records attributed to Lewis, C. B..

4 recordsLinked to original sources

bioRxiv2026

Enhanced inter-chain hydrogen bonding in the murine norovirus VP1 capsid leads to increased particle stability and delayed viral uncoating

Capsid stability is vital for virion survival as the capsid must withstand varying environmental challenges such as pH and temperature to allow the virus to reach a target cell. Noroviruses are non-enveloped, icosahedral, positive-sense RNA viruses of importance to human health globally, with no approved vaccine or antiviral available. Despite this, the molecular mechanisms behind norovirus capsid stability and capsid rearrangement prior to RNA translocation are understudied. Using murine norovirus as a model, we utilised thermal stress to create a thermally stable virus population. By introducing three identified substitutions in the major capsid protein VP1 from this virus population into an infectious clone, we were able to create a heat and pH stable virus that had delayed viral uncoating during the infectious lifecycle. Cryo-EM reconstructions of the triple substitution virus demonstrated that enhanced inter-chain hydrogen bonding was vital for increased capsid stability. Finally, mutagenesis to remove the enhanced inter-chain hydrogen bonding reverted capsid stability back to wild-type levels. This work contributes to fundamental calicivirus biology by demonstrating areas of importance in capsid stability down to amino acid resolution. Furthermore, this work could inform vaccine design for a thermostable norovirus vaccine in the future. Author SummaryNoroviruses cause gastroenteritis and globally contribute to the death of up to 250,000 people worldwide per annum and an estimated healthcare cost of $4 billion. Despite this, there is no vaccine or antiviral treatment available, thus more work needs to be conducted to understand the mechanisms that underpin the viral life cycle. The norovirus capsid is a meta-stable shell-like structure evolved to protect the viral RNA from the harsh external environment, until cellular triggers allow genome release to initiate infection of a host cell. However, the molecular interactions that are key for controlling this balance are relatively unstudied. In this report, we identify that hydrogen bonding at the capsid protomer-protomer interface are vital for maintaining this balance, with increased inter-molecular hydrogen bonding at three specific amino acids able to increase viral stability whilst still permitting infectious genome release. Furthermore, reducing inter-molecular hydrogen bonding at these crucial amino acids was able to reverse this mechanism. These results should inform future norovirus vaccine studies, where thermostable virus-like-particles are needed to overcome issues with cold-chain storage.

microbiology↗

bioRxiv2026

Inhibition of VP2-mediated entry: a potential antiviral strategy to treat or prevent calicivirus disease

The Caliciviridae include many notable human and animal pathogens, including norovirus and sapovirus, which cause outbreaks of acute gastroenteritis. We previously demonstrated that, following receptor engagement, feline calicivirus (FCV) assembles a portal structure at a unique capsid three-fold axis. This comprises twelve copies of the minor capsid protein VP2 and is essential for genome delivery. We designed a short peptide based on our structure data that occludes the VP2 binding sites on the capsid surface, to prevent assembly of the VP2 portal and thereby halt the viral entry mechanism. Incubation with low micromolar concentrations of the peptide considerably reduced the infectivity of two laboratory strains and four clinical isolates of FCV associated with respiratory or virulent-systemic disease. Cryo-electron microscopy structures of FCV virions complexed with the peptide confirmed that the peptide occupies the VP2 binding site on the major capsid protein VP1, preventing portal assembly and subsequent genome delivery. Our data show that targeting VP2 is a viable antiviral approach to preventing calicivirus infection, with potential for the treatment or prevention of norovirus disease.

microbiology↗

bioRxiv2025

Shedding dynamics of the Ross seal (Ommatophoca rossii) whiskers investigated through carbon and nitrogen bulk stable isotope composition

Understanding the trophic ecology of pinnipeds is essential to define their role in ecosystems and anticipate their responses as top predators to environmental changes. Incremental analyses of carbon ({delta}13C) and nitrogen ({delta}15N) stable isotopes along their whiskers provide valuable records of their foraging habitat and trophic level over time. The effectiveness of this approach relies on knowledge of species-specific whisker shedding dynamics and growth rates. We investigated the shedding dynamics of Ross seal (Ommatophoca rossii) whiskers and attempted to evaluate the time captured in these tissues by combining whiskers bulk{delta} 13C and{delta} 15N incremental measurements with satellite tracking data, collected after whisker growth. Our tracking data are consistent with previous studies, in that Ross seals migrate post-moult between the marginal ice zone and the Antarctic Polar Front. Stable isotope profiles of whiskers did not show the typical decrease in{delta} {superscript 1}3C and increase in{delta} {superscript 1}N values at the whiskers tip that would be expected if shedding coincided with the annual fur moult, when fasting typically occurs. The occurrence of similar isotope variations, which were offset between the left and right whiskers of the same individual in relation to distance from the muzzle, further suggest asynchronous, non-seasonal whisker shedding. Our inability to identify known cyclic phenological events (i.e., fasting periods or seasonal migrations) prevented the determination of the average growth rate of whiskers. The additional data on whisker shedding dynamics of Ross seals is a valuable first step in support of future ecological studies based on the whiskers of this species.

ecology↗

bioRxiv2022

Evidence of a novel viral membranefusion mechanism shared by theHepaci, Pegi and Pestiviruses

Enveloped viruses encode specialised glycoproteins that mediate fusion of viral and host membranes. Discovery and understanding of the molecular mechanisms of fusion has been achieved through structural analyses of glycoproteins from many different viruses, and yet the fusion mechanisms of some viral genera remain unknown. We have employed systematic genome annotation and AlphaFold modelling to predict the structures of the E1E2 glycoproteins from sixty viral species in the Hepaci, Pegi and Pestivirus genera. Whilst the predicted structure of E2 varied widely, E1 exhibited a very consistent fold across genera, despite little or no homology at the sequence level. Critically, the structure of E1 is unlike any other known viral glycoprotein. This is the first evidence that the Hepaci, Pegi and Pestiviruses possess a common and novel membrane fusion mechanism. Comparison of E1E2 models from various species reveals recurrent features that are likely to be mechanistically important and sheds light on the evolution of membrane fusion in these viral genera. These findings provide new fundamental understanding of viral membrane fusion and are relevant to structure-guided vaccinology.

microbiology↗