title: IFNλ is a potent anti-influenza therapeutic without the inflammatory side effects of IFNα 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 (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.
authors: Immunoregulation Laboratory, Mill Hill Laboratory, Francis Crick Institute, London, UK.
authors: Sophia
authors: S
authors: Davidson
authors: Immunoregulation Laboratory, Mill Hill Laboratory, Francis Crick Institute, London, UK.
authors: Teresa M
authors: 0000-0002-0298-1426
authors: TM
authors: McCabe
authors: Immunoregulation Laboratory, Mill Hill Laboratory, Francis Crick Institute, London, UK.
authors: Stefania
authors: 0000-0003-4676-8616
authors: S
authors: Crotta
authors: Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
authors: Hans Henrik
authors: HH
authors: Gad
authors: Refractory Respiratory Inflammation Discovery Performance Unit, Respiratory Therapy Area, GSK, Stevenage, UK.
authors: Edith M
authors: EM
authors: Hessel
authors: Refractory Respiratory Inflammation Discovery Performance Unit, Respiratory Therapy Area, GSK, Stevenage, UK.
authors: Soren
authors: 0000-0002-2850-5241
authors: S
authors: Beinke
authors: Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
authors: Rune
authors: 0000-0003-1159-066X
authors: R
authors: Hartmann
authors: Immunoregulation Laboratory, Mill Hill Laboratory, Francis Crick Institute, London, UK andreas.wack@crick.ac.uk.
authors: Andreas
authors: 0000-0001-5226-2991
authors: A
authors: Wack
mesh_terms: D000818:Animals; D016923:Cell Death; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000502:physiology; D006801:Humans; D009980:Influenza A virus / Q000302:isolation & purification; D016898:Interferon-alpha / Q000627:therapeutic use; D007378:Interleukins / Q000627:therapeutic use*; D007962:Leukocytes / Q000276:immunology; D008168:Lung / Q000473:pathology; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control / Q000821:virology; D016896:Treatment Outcome; D019562:Viral Load; D000095022:Interferon Lambda
chemical_list: D016207:Cytokines; D016898:Interferon-alpha; D007378:Interleukins; C579163:IFNL4 protein, human; D000095022:Interferon Lambda
keywords: immunopathology; infection; influenza; interferon alpha; interferon lambda