Poliovirus is a small RNA virus belonging to the genus Enterovirus of the family Picornaviridae. Poliovirus causes a unique human neurologic disease involving the destruction of motor neurons, which leads to paralysis and even death (poliomyelitis). In contrast to the Old World Monkeys (OWMs), most New World Monkeys (NWMs) are not susceptible to poliovirus (PV), regardless of the route of infection. We have investigated the molecular basis of restricted PV pathogenesis of NWMs with two kidney cell lines of NWMs, TMX (Tamarin) and NZP-60 (Marmoset), and characterized their PV receptor homologues. TMX cells were susceptible to infection by PV1 (Mahoney) and PV3 (Leon) but not by PV2 (Lansing). Binding studies to TMX cells indicated that the formation of PV/receptor complexes increases when measured first at 4C and then at 25C whereas PV2 did not significantly bind to TMX cells at either temperature. On the other hand, NZP-60 cells were not susceptible to infection by any of the PV serotypes. However, a low amount of PV1 bound to NZP-60 cells at 4C but there was no increase of binding at 25C. In contrast, both NWM cell lines supported genome replication and virion formation when transfected with viral RNAs of either serotype, an observation indicating that infection was blocked in receptor-virus interaction. To overcome the receptor block in marmoset cells, we substituted 3 amino acids in the marmoset receptor (nCD155), H80Q, N85S, and P87S, that occur in the human PV receptor, hCD155. Cells expressing the mutant receptor (L-nCD155mt) were now susceptible to infection with PV1, which correlated with an increase in PV1 bound receptor complexes from 4C to 25C. L-nCD155mt cells were, however, still resistant to PV2 and PV3. These data show that an increase in the formation of PV/receptor complexes, when measured at 4C and at 25C correlates with, and is an indicator of, successful infection at 37C, suggesting that the complex formed at 25C may be an intermediate in PV uptake. The virus infects humans by ingestion but the molecular mechanisms of oral pathogenesis are poorly understood. Except for monkeys, no animal models exist for the study of oral infection. Based on monkey studies, it has been determined that the initial step in PV infection and pathogenesis is the replication of the virus in tissues of the gastrointestinal tract, most likely in gut associated lymphoid tissues (GALT), but the precise sites of replication are not known. One difficulty with studying the early steps of PV pathogenesis is that in TgPVR21 mice, generated with human CD155 promoter and gene, CD155 is not expressed in the alimentary canal; hence, the TgPVR21 mice cannot be infected orally. Murine CD155 (mCD155; also known as Tage4), a member of the CD155/nectin family, has been accepted as the mouse orthologue of human CD155. The mCD155 does not serve as a functional PV receptor, nevertheless, the murine and human CD155 recognize same panel of ligands whenever examined: nectin-3, CD226, CD96 and vitronectin. Like human CD155, mCD155 lacks self adhesion and contributes substantially to the establishment of adheren juntions between epithelial cells. More importantly they are expressed in the GALT of human and mice in similar patterns. We describe here the generation of a transgenic mouse model in which the mCD155 promoter controls the expression of the CD155 coding region. The mCD155 tg mice show CD155 expression in brain, spinal cord, kidney and liver by western blot. The CD155 expression is detected in the GALT of the 3 and 6 week old mice by immunostaining. Infection by parenteral routes of the mCD155tg...