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

ABSTRACT Beyond a physical barrier, the lung epithelium provides an essential line of defense against infectious pathogens, such as influenza A viruses (IAVs), by producing 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 significant RELMɑ secretion by IAV-infected EpCAM+ epithelial cells. Both whole-body and club cell-specific RELMɑ-deficient mice ( Retnla −/− and Retnla ΔCC10 ) had significantly reduced infectious virus, specifically in epithelial cells, whereas the lung immune response was unaffected. RELMɑ treatment increased IAV infection of murine lung epithelial cell lines, and transcriptomic analysis indicated that RELMɑ-induced permissiveness to IAV was associated with cell-intrinsic changes in metabolic activity. Collectively, these studies suggest a direct non-immune role for RELMɑ in mediating a virus-permissive environment in epithelial cells. IMPORTANCE Seasonal influenza causes over 3 million cases of severe disease and an estimated 500,000 deaths worldwide annually, highlighting the need for new therapeutic targets. The host response to infection is a significant factor in determining influenza outcome and can be subverted by the virus. The epithelial barrier is the first line of defense and a target for influenza A viruses (IAVs), which seek to establish a permissive environment for their own growth, and these pathways could be targeted to control viral burden. Here, we identify RELMɑ, a new host factor that is induced in epithelial cells upon IAV infection and aids viral infection. Through RELMɑ-deficient mouse models, lung epithelial cell cultures, and gene expression analysis, we show that RELMɑ acts directly on epithelial cells to change cell metabolic pathways and promote viral growth. These findings provide a unique epithelial cell protein that can be inhibited to limit influenza infection.