Envelope adaptation drives dengue virus tropism in skin cells

RNA viruses pose significant major threats to global health due to their
high mutation rate and remarkable evolutionary adaptability. These
features enable the acquisition of new functions, including infection of
novel hosts and cell types and drug and immune evasion, making RNA viruses
persistent therapeutic challenges. Here, we investigated the adaptability
of dengue virus (DENV), one of the most prevalent RNA viruses, in
low-permissive skin cells, a cell type encountered early after
mosquito-transmission. Through serial passaging, we identified an amino
acid substitution at codon 327 in the viral envelope (E) protein that
markedly enhanced infectivity. Introduction of this substitution into
other antigenically similar dengue strains of the same DENV serotype also
increased infection efficiency. We propose that this enhanced phenotype is
driven by improved viral spread and depends on the overall E protein
structure, potentially linked to its higher-order organization. Mass
spectrometry analysis further revealed that the substitution did not alter
host-virus interactions. Together, our findings highlight a generalizable
strategy for probing viral host adaptability and predicting key mutations
that may drive changes in cellular tropism.