Journal Article

IFNλ is a potent anti‐influenza therapeutic without the inflammatory side effects of IFNα treatment

McCabe, Teresa M, Crotta, Stefania, Wack, Andreas, Davidson, Sophia, Gad, Hans Henrik, Beinke, Soren, Hessel, Edith M, Hartmann, Rune

2016

Overview

Influenza A virus (IAV)‐induced severe disease is characterized by infected lung epithelia, robust inflammatory responses and acute lung injury. Since type I interferon (IFNαβ) and type III interferon (IFNλ) are potent antiviral cytokines with immunomodulatory potential, we assessed their efficacy as IAV treatments. IFNλ treatment of IAV‐infected Mx1‐positive mice lowered viral load and protected from disease. IFNα treatment also restricted IAV replication but exacerbated disease. IFNα treatment increased pulmonary proinflammatory cytokine secretion, innate cell recruitment and epithelial cell death, unlike IFNλ‐treatment. IFNλ lacked the direct stimulatory activity of IFNα on immune cells. In epithelia, both IFNs induced antiviral genes but no inflammatory cytokines. Similarly, human airway epithelia responded to both IFNα and IFNλ by induction of antiviral genes but not of cytokines, while hPBMCs responded only to IFNα. The restriction of both IFNλ responsiveness and productive IAV replication to pulmonary epithelia allows IFNλ to limit IAV spread through antiviral gene induction in relevant cells without overstimulating the immune system and driving immunopathology. We propose IFNλ as a non‐inflammatory and hence superior treatment option for human IAV infection. Synopsis IFNα and IFNλ are both antiviral cytokines. IFNλ appears to confer better protection than IFNα 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 (IFNα) and lambda (IFNλ) protect from influenza virus infection when mice are treated prior to infection. When infected mice are treated therapeutically after onset of symptoms, IFNλ protects but IFNα aggravates disease. Both IFNα and IFNλ have antiviral effects, but IFNα also activates immune cells in the lung leading to immunopathology, while IFNλ does not. The response pattern to IFNα and IFNλ 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. Graphical Abstract IFNα and IFNλ are both antiviral cytokines. IFNλ appears to confer better protection than IFNα 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.

• Publisher: Nature Publishing Group UK,John Wiley & Sons, Inc,EMBO Press,John Wiley and Sons Inc,Springer Nature
• Subject: Analysis / Animals / B cells / Biological response modifiers / Cell Death / Complications and side effects / Cytokines / Cytokines - analysis / Disease Models, Animal / Drug dosages / Drug resistance / EMBO19 / EMBO23 / Epithelial cells / Epithelial Cells - physiology / Genes / Humans / Immune system / Immunomodulation / immunopathology / infection / Infections / Inflammation / Influenza / Influenza A / Influenza A virus - isolation & purification / Interferon / interferon alpha / interferon lambda / Interferon-alpha - therapeutic use / Interleukins - therapeutic use / Leukocytes - immunology / Lung - pathology / Lung diseases / Medical research / Mice / Mutation / Myxovirus resistance proteins / Orthomyxoviridae Infections - drug therapy / Orthomyxoviridae Infections - pathology / Orthomyxoviridae Infections - prevention & control / Orthomyxoviridae Infections - virology / Pandemics / Replication / Research Article / Respiratory tract / Treatment Outcome / Vaccines / Viral infections / Viral Load / Viruses / α-Interferon