AP-1 mediated lineage memory shapes viral resistance barriers in human skin

We used multi-color lineage tracing in a human primary organotypic skin model to reveal that viral resistance is encoded within specific cellular lineages. These lineages create distinct boundaries that block viral spread.

Our lineage analyses in vitro confirmed that viral susceptibility exhibits strong heritability across cell generations, with siblings and cousins displaying remarkably similar infection outcomes. ATAC and proteomics profiling of resistant and susceptible clones revealed distinct epigenomic and proteomic states, with the transcription factor AP-1 emerging as a central regulator of lineage-encoded viral resistance. Inducing AP-1 activity rendered cells resistant to viral infection, further confirming its role in mediating resistance memory.