Norovirus Polymerase Fidelity Contributes to Viral Transmission In Vivo

Armando Arias Esteban, Lucy Thorne, Elsa Ghurburrun, Dalan Bailey, Ian Goodfellow

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    Abstract

    Intrahost genetic diversity and replication error rates are intricately linked to RNA virus pathogenesis, with alterations in viral polymerase fidelity typically leading to attenuation during infections in vivo. We have previously shown that norovirus intrahost genetic diversity also influences viral pathogenesis using the murine norovirus model, as increasing viral mutation frequency using a mutagenic nucleoside resulted in clearance of a persistent infection in mice. Given the role of replication fidelity and genetic diversity in pathogenesis, we have now investigated whether polymerase fidelity can also impact virus transmission between susceptible hosts. We have identified a high-fidelity norovirus RNA-dependent RNA polymerase mutant (I391L) which displays delayed replication kinetics in vivo but not in cell culture. The I391L polymerase mutant also exhibited lower transmission rates between susceptible hosts than the wild-type virus and, most notably, another replication defective mutant that has wild-type levels of polymerase fidelity. These results provide the first experimental evidence that norovirus polymerase fidelity contributes to virus transmission between hosts and that maintaining diversity is important for the establishment of infection. This work supports the hypothesis that the reduced polymerase fidelity of the pandemic GII.4 human norovirus isolates may contribute to their global dominance.
    Original languageEnglish
    Article number00279-16
    JournalmSphere
    Volume1
    Issue number5
    Number of pages11
    ISSN2379-5042
    DOIs
    Publication statusPublished - 2016

    Keywords

    • RNA polymerases
    • Noroviruses
    • Polymerase fidelity
    • Quasispecies
    • Virus transmission

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