IFN is a potent anti-influenza therapeutic without the inflammatory side effects of IFN treatment

Influenza A virus (IAV)-induced severe disease is characterized by infected lung epithelia, robust inflammatory responses and acute lung injury. Since type I interferon (IFN) and type III interferon (IFN) are potent antiviral cytokines with immunomodulatory potential, we assessed their efficacy as IAV treatments. IFN treatment of IAV-infected Mx1-positive mice lowered viral load and protected from disease. IFN treatment also restricted IAV replication but exacerbated disease. IFN treatment increased pulmonary proinflammatory cytokine secretion, innate cell recruitment and epithelial cell death, unlike IFN-treatment. IFN lacked the direct stimulatory activity of IFN on immune cells. In epithelia, both IFNs induced antiviral genes but no inflammatory cytokines. Similarly, human airway epithelia responded to both IFN and IFN by induction of antiviral genes but not of cytokines, while hPBMCs responded only to IFN. The restriction of both IFN responsiveness and productive IAV replication to pulmonary epithelia allows IFN to limit IAV spread through antiviral gene induction in relevant cells without overstimulating the immune system and driving immunopathology. We propose IFN as a non-inflammatory and hence superior treatment option for human IAV infection.