Abstract
Murine norovirus (MNV) is widely used as a model for studying norovirus biology. While MNV isolates vary in their pathogenesis, infection of immunocompetent mice mostly results in persistent infection. The ability of a virus to establish a persistent infection is dependent on its ability to subvert or avoid the host immune response. Previously, we described the identification and characterization of virulence factor 1 (VF1) in MNV, and demonstrated its role as an innate immune antagonist. Here, we explore the role of VF1 during persistent MNV infection in an immunocompetent host. Using reverse genetics, we generated MNV-3 viruses carrying a single or a triple termination codon inserted in the VF1 ORF. VF1-deleted MNV-3 replicated to comparable levels to the wildtype virus in tissue culture. Comparative studies between MNV-3 and an acute MNV-1 strain show that MNV-3 VF1 exerts the same functions as MNV-1 VF1, but with reduced potency. C57BL/6 mice infected with VF1-deleted MNV-3 showed significantly reduced replication kinetics during the acute phase of the infection, but viral loads rapidly reached the levels seen in mice infected with wildtype virus after phenotypic restoration of VF1 expression. Infection with an MNV-3 mutant that had three termination codons inserted into VF1, in which reversion was suppressed, resulted in consistently lower replication throughout a 3 month persistent infection in mice, suggesting a role for VF1 in viral fitness in vivo. Our results indicate that VF1 expressed by a persistent strain of MNV also functions to antagonize the innate response to infection. We found that VF1 is not essential for viral persistence, but instead contributes to viral fitness in mice. These data fit with the hypothesis that noroviruses utilize multiple mechanisms to avoid and/or control the host response to infection and that VF1 is just one component of this.
Highlights
With figures upwards of 19 million cases annually, human norovirus (HuNoV) is increasingly becoming the leading causative agent of gastroenteritis [1,2,3,4]
We have previously demonstrated that virulence factor 1 (VF1), encoded by the murine norovirus (MNV)-1 ORF4 (Fig. 1a), is expressed by 9 h post-infection of murine macrophage cultured cells, that it localizes to the mitochondria, and that it antagonizes the induction of IFN-β [19]
Western blot analysis showed that VF1 expression was readily detected in both MNV-1.CW1 acute and attenuated strain (MNV-1) and MNV-3 infected cells (Fig. 1b)
Summary
With figures upwards of 19 million cases annually, human norovirus (HuNoV) is increasingly becoming the leading causative agent of gastroenteritis [1,2,3,4]. There are currently no vaccines available against HuNoV, largely due to long-standing difficulties in culturing the virus in vitro and the lack of a robust animal model that together have impeded the identification of the correlates of protection. The establishment of reverse genetics systems, the ability to replicate in cultured cells with a tropism for macrophages and dendritic cells, and the availability of a robust homologous small animal model have made MNV a model of choice for studying norovirus pathogenesis [5, 10,11,12]. While some strains cause an acute infection that is cleared within 7 days in immunocompetent mice, other strains are able to persist for up to 9 months [15]. MNV has proven invaluable as a tool to dissect host and viral factors that contribute to viral persistence and
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