TRIM47 inhibits murine norovirus replication in a strain-dependent manner

Human norovirus is the leading cause of gastroenteritis worldwide. Norovirus exhibits remarkable genetic diversity. Understanding the impact of genetic diversity on infection and immunity has been challenging due to the difficulties in in vitro cultivation and the current lack of a small animal model. Murine norovirus (MNV) has emerged as a premier model system to investigate norovirus biology. Here, we identify TRIM47 as a host restriction factor that potently inhibits MNV infection in a strain-dependent manner. We determine that TRIM47 expression inhibits an early stage of the viral life cycle of the MNV strain CR6 (MNV^CR6), while the replication of the closely related strain CW3 (MNV^CW3) is not restricted by TRIM47. MNV^CW3 causes an acute infection that spreads beyond intestinal tissues and is lethal to immunodeficient mice. In contrast, MNV^CR6 fails to spread to systemic tissues but establishes a persistent infection by infecting intestinal tuft cells. Using a forward genetic screen, we determine that genetic variation within the nonstructural protein 1 (NS1) accounts for this differential sensitivity of MNV strains to TRIM47. While most TRIM-containing proteins promote the ubiquitination and degradation of their targets, TRIM47 does neither. Instead, TRIM47 promotes the deubiquitination of the NS1/2 precursor protein. Our data provide new insight into a potential antiviral gene and mechanistic insight into norovirus evolution that may impact viral tropism.IMPORTANCEViruses exist as genetically heterogeneous populations. Understanding the contribution of viral genetic variation to infection outcomes is critical in predicting emerging viruses and their variants. Noroviruses are genetically diverse, but human norovirus has been technically challenging to study. In this study, we use the model system murine norovirus to identify a viral strain-specific restriction mechanism where a host gene can specifically restrict one strain of the virus but has no impact on a closely related strain. Dissecting the mechanism of this specificity provides insight into viral diversity and possible host restriction pathways.