Beschreibung:
<jats:p>Until recently, our understanding of the cellular tropism of human norovirus (HuNoV), a major cause of viral gastroenteritis, has been limited. Immune cells and intestinal epithelial cells (IECs) have been proposed as targets of HuNoV replication <jats:italic>in vivo</jats:italic>, although the contribution of each to pathogenesis and transmission is unknown. Murine norovirus (MNV) is widely used as a surrogate model for HuNoV, as it replicates in cultured immune cells. The importance of the complete MNV immune cell tropism <jats:italic>in vivo</jats:italic> has not been determined. Recent work has linked replication in IECs to viral persistence <jats:italic>in vivo</jats:italic>. MNV provides a model to assess the relative contribution of each cell tropism to viral replication in immunocompetent native hosts. Here we exploited cell-specific microRNAs to control MNV replication, through insertion of microRNA target sequences into the MNV genome. We demonstrated the utility of this approach for MNV <jats:italic>in vitro</jats:italic> by selectively reducing replication in microglial cells, using microglial-specific miR-467c. We then showed that inserting a target sequence for the haematopoietic-specific miR-142-3p abrogated replication in a macrophage cell line. The presence of a target sequence for either miR-142-3p or IEC miR-215 significantly reduced viral secretion during the early stages of a persistent infection in immunocompetent mice, confirming that both cell types support viral replication <jats:italic>in vivo.</jats:italic> This study provides additional evidence that MNV shares the IEC tropism of HuNoVs <jats:italic>in vivo</jats:italic>, and now provides a model to dissect the contribution of replication in each cell type to viral pathogenesis and transmission in a native host.</jats:p>