Bridging the gap: ex vivo human skin explants for mechanistic studies of arboviruses.

Arboviruses such as dengue (DENV), Zika (ZIKV), chikungunya virus (CHIKV), and Crimean-Congo hemorrhagic fever (CCHFV) have been extensively studied in cell culture and animal models, yet how these findings translate to early infection events in human skin remains largely uncertain. Standard monolayers lack the stratified architecture and resident immune cells of the epidermis and dermis, while rodent skin differs markedly in structure, immunity, and mosquito interactions. Ex vivo human skin explants bridge this translational gap by preserving the native cutaneous microenvironment, including keratinocytes, fibroblasts, Langerhans cells, dermal dendritic cells, and extracellular matrix. Thereby, they enable infection under conditions that approximate natural mosquito bite transmission, including the deposition of virus and saliva during mosquito probing and the accompanying immunomodulatory effects. This review synthesizes insights from human skin explant models and contrasts them with monolayer systems, showing how intact skin architecture reshapes early viral behavior and innate immune activation. It further highlights innovations - such as fluorescent saliva reporter mosquitoes and engineered vascular skin platforms - that enable tracking of arbovirus delivery and host responses at the vector-skin interface. These platforms hold promise not only for defining early determinants of human susceptibility, especially in the light of the recently identified arbovirus receptors, but also for testing topical or locally acting countermeasures at the true portal of viral entry. Major gaps remain, including the absence of blood circulation in currently available human skin explants, underscoring the need to extend skin explant approaches across the broader landscape of vector-borne pathogens.