Human adenoviruses (AdV) are highly contagious and account for ~2-15% of the respiratory tract infections worldwide, depending on age and country (1, 2). They are transmitted by respiratory droplets, person-to-person contacts or contaminated surfaces. AdVs infect epithelial cells and immune cells. The former give rise to high levels of progeny, and viremic dissemination through lytic or nonlytic pathways (3, 4), affected by cell state (5), and cell cycle (6, 7). Infections of immune cell, in contrast, yield low amounts of progeny suggesting strong anti-viral defense (8, 9). Here, we discuss how inducible-pluripotent stem cell (iPSC)-derived human macrophages restrict infection by AdV-C5, a virus-type known to persist in immune cells of the gastro-intestinal tract of children, and cause life-threatening conditions upon immuno-suppression. I also discuss how AdV transactivation turns macrophage infections from a restricted to a productive state, with potential implications for pathogenesis. Beyond transcriptional control of AdV-C5 progeny formation by interferon-mediated repression of the E1A enhancer/promoter inducing a persistence state in normal human dermal fibroblasts (10), we present cell biological observations suggesting a mechanism for switching between lytic and nonlytic AdV egress in epithelial cells. The results have implications for oncolytic viral therapies, and modulating the inflammatory response triggered by AdV infections.

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