Norovirus polymerase fidelity contributes to viral transmission in vivo: Increased fidelity reduces virus transmission

Intra-host 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 intra-host 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. This mutant also exhibited slower rates of transmission between susceptible hosts in comparison to the wild type virus and, most notably with a replication defective mutant that has wild-type 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.