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