Skin is a major target tissue of herpes simplex virus 1 (HSV-1), and we are only beginning to understand how individual receptors contribute to the initiation of
infection in tissue. We recently demonstrated the impact of the receptors
nectin-1 and
herpesvirus entry mediator (HVEM) for entry of HSV-1 into murine epidermis. Here, we focus on viral invasion into the dermis, a further critical target tissue in vivo In principle, murine dermal fibroblasts are highly susceptible to HSV-1, and we previously showed that
nectin-1 and HVEM can act as alternative receptors. To characterize their contribution as receptors in dermal tissue, we established an ex vivo
infection assay of murine dermis. Only after separation of the epidermis from the dermis, we observed single infected cells in the upper dermis from juvenile mice at 5 h postinfection with increasing numbers of infected cells at later times. While nectin-1-expressing cells were less frequently detected, we found HVEM expressed on most cells of juvenile dermis. The comparison of
infection efficiency during aging revealed a strong delay in the onset of
infection in the dermis from aged mice. This observation correlated with a decrease in nectin-1-expressing fibroblasts during aging while the number of HVEM-expressing cells remained stable. Accordingly, aged nectin-1-deficient dermis was less susceptible to HSV-1 than the dermis from control mice. Thus, we conclude that the reduced availability of
nectin-1 in aged dermis is a key contributor to a decrease in
infection efficiency during aging.IMPORTANCE HSV-1 is a prevalent human pathogen which invades skin and mucocutaneous linings. So far, the underlying mechanisms of how the virus invades tissue, reaches its receptors, and initiates
infection are still unresolved. To unravel the mechanical prerequisites that limit or favor viral invasion into tissue, we need to understand the contribution of the receptors that are involved in viral internalization. Here, we investigated the invasion process into murine dermis with the focus on receptor availability and found that
infection efficiency decreases in aging mice. Based on studies of the expression of the receptors
nectin-1 and HVEM, we suggest that the decreasing number of nectin-1-expressing fibroblasts leads to a delayed onset of
infection in the dermis from aged compared to juvenile mice. Our results imply that the level of
infection efficiency in murine dermis is closely linked to the availability of the receptor
nectin-1 and can change during aging.