An innate defense peptide BPIFA1/SPLUNC1 restricts influenza A virus infection

The airway epithelium secretes proteins that function in innate defense against infection. BPI fold-containing family member A1 (BPIFA1) is secreted into airways and has a protective role during bacterial infections, but it is not known whether it also has an antiviral role. To determine a role in host defense against influenza A virus (IAV) infection and to find the underlying defense mechanism we developed transgenic mouse models that are deficient in BPIFA1 and used these, in combination with in vitro 3D mouse tracheal epithelial cell (mTEC) cultures, to investigate its antiviral properties. We show that BPIFA1 has a significant role in mucosal defense against IAV infection. BPIFA1 secretion was highly modulated after IAV infection. Mice deficient in BPIFA1 lost more weight after infection, supported a higher viral load and virus reached the peripheral lung earlier, indicative of a defect in the control of infection. Further analysis using mTEC cultures showed that BPIFA1-deficient cells bound more virus particles, displayed increased nuclear import of IAV ribonucleoprotein complexes and supported higher levels of viral replication. Our results identify a critical role for BPIFA1 in the initial phase of infection by inhibiting the binding and entry of IAV into airway epithelial cells.