RELMα establishes a permissive environment for influenza infection through direct effects on lung epithelial cells

Beyond a physical barrier, the lung epithelium provides an essential line of defense against infectious pathogens, such as Influenza A viruses (IAV), through antimicrobial factors and triggering innate and adaptive immunity. On the other hand, IAV infects lung epithelial cells and manipulates their function to establish a non-protective, permissive environment. Identification of epithelial factors and pathways that can be targeted to restore optimal immunity would provide new therapeutic options against IAV. Here, we demonstrate an unexpected non-immune function for the cytokine RELMɑ in mediating a permissive environment for IAV infection through lung epithelial cell-intrinsic effects. Murine infection with IAV A/California/04/2009 (H1N1) led to the significant RELMɑ secretion by IAV-infected EpCam+ epithelial cells. Both constitutive and club cell-specific RELMɑ-deficient mice (Retnla-/- and RetnlaΔCC10) had significantly reduced IAV virus, specifically in epithelial cells, whereas the lung immune response was unaffected. RELMɑ treatment increased IAV infection of murine lung epithelial cell lines (MLE), and transcriptomic analysis indicated that RELMɑ-induced permissiveness to IAV was associated with cell-intrinsic changes in metabolic activity. Collectively, these studies indicate a direct non-immune role for RELMɑ in mediating a virus-permissive environment in epithelial cells potentially through modulation of cellular metabolism.