Microfold (M) cells are specialized intestinal epithelial cells that internalize particulate antigens and aid in the establishment of immune responses to enteric pathogens. intestine. IMPORTANCE To successfully infect their hosts, pathogens that infect via the gastrointestinal tract must overcome the multilayered system of host defenses. Microfold (M) cells are specialized intestinal epithelial cells that internalize particulate antigens and aid in the establishment of immune responses to enteric pathogens. Virus particles have been observed within M cells. However, it is not known whether viruses use M cells to initiate a productive infection. To address this question, we use MNV and reovirus, two enteric viruses that replicate in different cell types in the intestine, intestinal epithelial cells for reovirus and intestinal mononuclear phagocytes for MNV. Interestingly, MNV- and reovirus-infected mice depleted of M cells showed reduced viral loads in the intestine. Thus, our work demonstrates the importance of M cells in the pathogenesis of enteric viruses irrespective of the target cell type in which the virus replicates. INTRODUCTION The gastrointestinal (GI) tract, being the largest mucosal surface in the body, forms a barrier between the interior and exterior milieu. Although multiple protective mechanisms are present, enteric viruses have evolved strategies to overcome this barrier and infect the host. Some enteric viruses enter the host by directly infecting enterocytes, e.g., rotavirus (1). Alternatively, microfold (M) cells have been proposed as a route of viral entry after visualization of selective uptake of MG-132 kinase inhibitor poliovirus and reovirus particles by Peyer’s patch (PP) M cells (2, 3). However, direct evidence demonstrating that M cells are required for the establishment of a productive virus infection is usually lacking. M cells are specialized epithelial cells that are mostly located in the follicle-associated epithelium (FAE) of organized lymphoid tissues like PPs. However, M cells also are found in intestinal villi, although villous M cells are less abundant than PP M cells (4). M cells selectively bind and endocytose IgA (5) and selectively express glycosylphosphatidylinositol-anchored glycoprotein 2 (GP2) (6). Mouse M cells also react with the agglutinin-I (UEA-I) lectin, which recognizes 1,2 fucose (7). M cells arise from individual stem cells in the crypt (8). Development of M cells depends on MG-132 kinase inhibitor the receptor activator of NF-B ligand (RANKL), which is usually expressed by subepithelial stromal cells in the PP domes (9, 10). Antibody-mediated neutralization of RANKL in wild-type mice transiently eliminates most PP M cells, while systemic administration of RANKL to RANKL-deficient mice restores PP M cells and induces differentiation of villous M cells (9). M cells function to sample antigens in the intestinal lumen for immune surveillance, including microorganisms and inert particles (e.g., latex beads) (11,C13). For MG-132 kinase inhibitor example, the bacterial pathogens serovar Typhimurium, exploit M cells to invade the host and establish infections (14,C17). In the case of model of the FAE demonstrate that MNV is usually transported across a polarized intestinal epithelial monolayer using M-like cells (28). However, how MNV crosses the intestinal epithelial barrier to reach the underlying permissive macrophages and dendritic cells is Rabbit Polyclonal to MERTK not known. Mammalian reoviruses are another widely used model for studies of viral pathogenesis (29). MG-132 kinase inhibitor Reoviruses are nonenveloped, segmented, double-stranded RNA viruses that cause disease in the very young but do not produce symptoms in adults (30). Reoviruses are classified into three serotypes represented by the prototype strains, type 1 Lang (T1L), type 2 Jones (T2J), and type 3 Dearing (T3D). While T1L and T3D differ in pathways of virus spread (hematogenous versus neural, respectively) (31), the primary site of replication for both strains in perorally inoculated newborn mice are intestinal enterocytes at the villus tips (32). T1L binds to 2,3-linked sialic acid-containing glycans on.