Oral norovirus infection is blocked in mice lacking Peyer's patches and mature M cells

A critical early step in murine norovirus (MNV) pathogenesis is crossing the intestinal epithelial barrier to reach the target cells for replication, i.e., macrophages, dendritic cells, and B cells. Our previous work showed that MNV replication decreases in the intestines of mice conditionally depleted of microfold (M) cells. To define the importance of Peyer's patch (PP)Mcells during MNV pathogenesis, we used a model of BALB/c mice deficient in recombination-activating gene 2 (Rag2) and the common gamma chain (γc) (Rag-γc^-/-), which lack gut-associated lymphoid tissues (GALT), such as Peyer's patches, and mature GP2⁺ Mcells. Rag-γc^-/- mice were infected intraperitoneally or perorally with MNV-1 or CR3 for 24 or 72 h. Although the intestinal laminae propriae of Rag-γc^-/- mice have a higher frequency of certain MNV target cells (dendritic cells and macrophages) than those of wild-type mice and lack others (B cells), Rag-γc^-/- and wild-type BALB/c mice showed relatively similar viral loads in the intestine following infection by the intraperitoneal route, which provides direct access to target cells. However, Rag-γc^-/- mice were not productively infected with MNV by the oral route, in which virions must cross the intestinal epithelial barrier. These data are consistent with a model whereby PPMcells are the primary route by which MNV crosses the intestinal epithelia of BALB/c mice.