IFN λ is a potent anti‐influenza therapeutic without the inflammatory side effects of IFN α treatment

Abstract

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 αβ) and type III interferon ( IFN λ) are potent antiviral cytokines with immunomodulatory potential, we assessed their efficacy as IAV treatments. IFN λ treatment of IAV ‐infected Mx1‐positive mice lowered viral load and protected from disease. IFN α treatment also restricted IAV replication but exacerbated disease. IFN α treatment increased pulmonary proinflammatory cytokine secretion, innate cell recruitment and epithelial cell death, unlike IFN λ‐treatment. IFN λ lacked the direct stimulatory activity of IFN α on immune cells. In epithelia, both IFN s induced antiviral genes but no inflammatory cytokines. Similarly, human airway epithelia responded to both IFN α and IFN λ by induction of antiviral genes but not of cytokines, while hPBMC s responded only to IFN α. The restriction of both IFN λ responsiveness and productive IAV replication to pulmonary epithelia allows IFN λ to limit IAV spread through antiviral gene induction in relevant cells without overstimulating the immune system and driving immunopathology. We propose IFN λ as a non‐inflammatory and hence superior treatment option for human IAV infection. image IFN α and IFN λ are both antiviral cytokines. IFN λ appears to confer better protection than IFN α in influenza experimentally infected organisms, as it helps control the virus in infected target cells in airway epithelia, and does not enhance inflammation in the lung. Both interferon alpha ( IFN α) and lambda ( IFN λ) protect from influenza virus infection when mice are treated prior to infection. When infected mice are treated therapeutically after onset of symptoms, IFN λ protects but IFN α aggravates disease. Both IFN α and IFN λ have antiviral effects, but IFN α also activates immune cells in the lung leading to immunopathology, while IFN λ does not. The response pattern to IFN α and IFN λ of human immune cells and lung epithelia is identical to that of mouse cells, strongly suggesting that the same effects would be found in humans.