Influenza A virus impairs antimicrobial molecules production in vitro in lung epithelial cells and in murine lung infection

Introduction: The role of antimicrobial molecules (AMM) is poorly defined in Influenza A (IAV) infections. We studied here their modulation following IAV infection in vitro and in vivo. Methods: A549, NCI-H292, BEAS-2B epithelial cells were infected with IAV +/- IL-1s and several cytokines (IL-8, CCL-5, IFN s) and antimicrobial molecules (HBD1, HBD2, HBD3, LL-37, Lcn2, S100A8, S100A9, elafin) levels were measured by q-PCR and ELISA. In parallel, mice were infected intratracheally with IAV (or PBS as control). 96hrs later, mice were given adenovirus (Ad)-elafin and 100 ng of mIL-1s i.t (or PBS as control), and inflammation was assessed 16hrs later. Results: 1) Basal expression of AMMs was higher in NCI-H292 (q-PCR dCT : between -3 and 12), and in all cell lines, HBD1 and elafin levels were the highest (dCT -2 and +2, respectively). IAV up-regulated elafin mRNA in A549 cells (20X), whereas protein induction was less induced (1-2X). By contrast, IL-1s up-regulated equally A549-derived mRNA and elafin protein (about 1000X). 2) IAV induced IL-8, CCL-5 and IFN s, both at the mRNA and protein levels. Interestingly, IAV significantly induced Lcn2 and elafin mRNA but down-regulated protein levels (from 4,000 to 1,000 pg/ml). 3) In vivo, IL-1s increased IAV-mediated inflammation, while specifically down-regulating antimicrobial molecules production. Strikingly, among all the mediators measured, IAV mostly down-regulated IL-1s-mediated elafin protein production (3 fold decrease). Conclusion: We show that IAV modulates elafin and Lcn2 expression, at homeostasis, and after IL-1s stimulation (modeling sterile inflammation). This may have important implications in viral pneumonia.