Amino acid substitutions in norovirus VP1 dictate cell tropism via an attachment process dependent on membrane mobility.

Autor:	Mills JT; Astbury Centre for Structural Molecular Biology, School of Molecular & Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK., Minogue SC; Astbury Centre for Structural Molecular Biology, School of Molecular & Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK., Snowden JS; Astbury Centre for Structural Molecular Biology, School of Molecular & Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK., Arden WKC; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48130, USA., Rowlands DJ; Astbury Centre for Structural Molecular Biology, School of Molecular & Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK., Stonehouse NJ; Astbury Centre for Structural Molecular Biology, School of Molecular & Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK., Wobus CE; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48130, USA., Herod MR; Astbury Centre for Structural Molecular Biology, School of Molecular & Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Feb 17. Date of Electronic Publication: 2023 Feb 17.
DOI:	10.1101/2023.02.17.528071
Abstrakt:	Viruses interact with receptors on the cell surface to initiate and co-ordinate infection. The distribution of receptors on host cells can be a key determinant of viral tropism and host infection. Unravelling the complex nature of virus-receptor interactions is, therefore, of fundamental importance to understanding viral pathogenesis. Noroviruses are non-enveloped, icosahedral, positive-sense RNA viruses of global importance to human health, with no approved vaccine or antiviral agent available. Here we use murine norovirus as a model for the study of molecular mechanisms of virus-receptor interactions. We show that variation at a single amino acid residue in the major viral capsid protein had a key impact on the interaction between virus and receptor. This variation did not affect virion production or virus growth kinetics, but a specific amino acid was rapidly selected through evolution experiments, and significantly improved cellular attachment when infecting immune cells in suspension. However, reducing plasma membrane mobility counteracted this phenotype, providing insight into for the role of membrane fluidity and receptor recruitment in norovirus cellular attachment. When the infectivity of a panel of recombinant viruses with single amino acid variations was compared in vivo , there were significant differences in the distribution of viruses in a murine model, demonstrating a role in cellular tropism in vivo . Overall, these results highlight the importance of lipid rafts and virus-induced receptor recruitment in viral infection, as well as how capsid evolution can greatly influence cellular tropism, within-host spread and pathogenicity. Competing Interests: Conflicts of interest The authors declare no conflicts of interest.
Databáze:	MEDLINE
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