Neuropilin-1 expression modulates infection susceptibility to murine cytomegalovirus at the materno-fetal interface

Human cytomegalovirus (HCMV) is the leading infectious cause of congenital disease, but the mechanisms governing vertical transmission remain poorly defined. Murine cytomegalovirus (MCMV) infection in mice is a widely used model to study pathogenesis <i>in vivo</i>. However, the mouse model cannot be used to study congenital infection as viral transmission from mother to fetus <i>in utero</i> does not occur. In this study, we investigated tissue-specific features of the murine materno-fetal barrier that may restrict viral infection. Following high-dose intravenous challenge of wild-type and severely immunocompromised pregnant mice, MCMV replicated efficiently in the maternal liver but infected only a few cells in the placenta, suggesting an intrinsic resistance. <i>Ex vivo</i> analyses of primary placental cells, trophoblast stem cells, and a trophoblast cell line revealed a low susceptibility to MCMV infection compared to other permissive cell types. The resistance of trophoblast cells to MCMV infection correlated with the absence of neuropilin-1 (NRP1), a cellular receptor required for efficient infection of several cell types. Enforced expression of NRP1 in trophoblast cells increased their susceptibility to MCMV infection and replication, suggesting that the resistance of trophoblast cells to MCMV infection is caused by the lack of a critical receptor. These findings further suggest that, in addition to immune-mediated restrictions, cell-intrinsic resistance limits MCMV infection and transmission at the murine materno-fetal interface.IMPORTANCECongenital cytomegalovirus (CMV) infection is a major cause of developmental disabilities in newborns, yet the biological factors that influence transmission from mother to fetus remain unclear. In this study, we demonstrate that trophoblast cells of the murine placenta are naturally resistant to CMV infection as they lack expression of a host protein, neuropilin-1 (NRP1), that the virus requires for entry. By introducing this protein into resistant cells, we demonstrated that susceptibility to infection can be reinstated, indicating that the absence of NRP1 plays a key protective role at the materno-fetal barrier. These results provide insight into why mice rarely transmit CMV to their offspring and how species-specific differences in placental biology shape susceptibility. Understanding these mechanisms will aid in refining animal models and may help identify new targets to prevent congenital infection in humans.