An immune-poised state of human bronchial epithelial cells mediates defense against RSV in adults.

Respiratory syncytial virus (RSV) impairs STAT3 activation in infected ciliated cells in infants, but not adults, causing apoptosis to facilitate virus spread. How age regulates the STAT3 response to RSV in human bronchial epithelial cells (BEpiCs) is unknown. Here, we identify an age-associated immune-poised physiological state in human bronchial basal stem cells (BSCs) and progeny BEpiCs, rendering robust RIG-I to guard against the inactivation of RIG-I-STAT3 signaling by RSV nonstructural protein 2. In contrast, infant BEpiCs are vulnerable to such inactivation by RSV due to lower RIG-I levels. We show that acute respiratory viral infection in specific pathogen-free mice, rather than physical age, triggers sustained epigenetic and transcriptomic remodeling in BEpiCs that resembles age-associated changes in human BEpiCs. In addition, cytokine pretreatment of human neonatal BSCs induces an adult-like immune-poised state that is maintained in progeny BEpiCs to defend against RSV. Therefore, respiratory infection and inflammation during a lifetime imparts the effect of age to BSCs, which fortifies RIG-I in progeny cells to mitigate RSV infection.