Transcriptional transactivation turns human hiPSC-macrophages into an adenovirus producing cell state

This contains the raw data of the publication "Transcriptional transactivation turns human hiPSC-macrophages into an adenovirus producing cell state". Human adenoviruses (AdV) manifest lytic infections of epithelial cells and viremia, and persist in lymphoid cells of the gastrointestinal tract. They cause life-threatening conditions upon immunosuppression, but little is known how macrophages conduct first-in-line AdV defense. Single-cell, single-virus experiments show that AdV-C5 entry into induced-pluripotent stem cell (iPSC)-derived human macrophages is attenuated at cell binding and endosomal escape. A significant fraction of the double-stranded viral DNA (vDNA) reaches the cell nucleus though, where it, however, fails to efficiently express the immediate early viral epigenetic regulator E1A. Surprisingly, E1A transcription of silenced vDNA was rescued by E1A expression from a heterologous promoter of co- or super-infecting AdV, and allowed for full viral replication and progeny formation, even days post infection, indicating long-lived infectivity of vDNA. Bulk RNA-seq and over-representation analyses for biological processes showed that attenuated single WT-AdV-C5 infections upregulated macrophage signaling, defense and proinflammatory genes, whereas productive coinfections upregulated pathways linked to DNA replication, and cell signaling. Together, our data show that human iPSC-macrophages restrict or enable productive AdV-C infections depending on cell state but independent of IFN, raising the possibility that macrophages function as a reservoir for AdV in humans, and reactivate dormant virus by epigenetic signals.