IFN-gamma signaling early during infection dramatically enhances antiviral programs in epithelial cells

To examine the impact of IFNγ signaling on human airway epithelial cells during influenza virus infection, we used differentiated air–liquid interface (ALI) cultures of normal human bronchial epithelial cells. Cultures were infected with influenza A/Netherlands/602/2009 (H1N1) and treated with recombinant IFNγ 4 hours post-infection. At 18 hours post-infection, basal, secretory, and ciliated epithelial cells were separated by FACS and analyzed by bulk RNA sequencing. IFNγ treatment after infection induced a distinct transcriptional signature across all epithelial subsets compared to infection alone, with basal cells showing the strongest transcriptional response. These data provide insight into epithelial subset–specific responses to IFNγ in the context of viral infection and reveal how early cytokine signaling can enhance antiviral programs in the human airway epithelium.