LAUSR

Significance We still have an incomplete understanding of the proteins influenza A virus (IAV) uses to enter the host cell. Here we demonstrate that IAV entry is diminished in the absence of transferrin receptor 1 (TfR1). Consequently, pharmacological targeting of TfR1 efficiently interferes with IAV replication. While this process could be mediated by an interaction of IAV HA with glycosylated TfR1, a “headless” TfR1 mutant still functions as a host entry factor for IAV in trans. Our “revolving door” model provides a plausible explanation as to why IAV is capable of entering such a broad range of cell types in culture and why the adaptation of the zoonotic avian IAV to mammalian cells involves primarily an adjustment to attachment factors rather than the entry machinery.