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

EMBO molecular medicine, 2016-09, Vol.8 (9), p.1099-1112 [Peer Reviewed Journal]

2016 The Authors. Published under the terms of the CC BY 4.0 license ;2016 The Authors. Published under the terms of the CC BY 4.0 license. ;COPYRIGHT 2016 John Wiley & Sons, Inc. ;2016. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. ;ISSN: 1757-4676 ;EISSN: 1757-4684 ;DOI: 10.15252/emmm.201606413 ;PMID: 27520969

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Title:
IFNλ is a potent anti‐influenza therapeutic without the inflammatory side effects of IFNα treatment
Author: Davidson, Sophia ; McCabe, Teresa M ; Crotta, Stefania ; Gad, Hans Henrik ; Hessel, Edith M ; Beinke, Soren ; Hartmann, Rune ; Wack, Andreas
Subjects: Analysis ; Animals ; B cells ; Biological response modifiers ; Cell Death ; Complications and side effects ; Cytokines ; Cytokines - analysis ; Disease Models, Animal ; Drug dosages ; Drug resistance ; 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 ; Respiratory tract ; Treatment Outcome ; Vaccines ; Viral infections ; Viral Load ; Viruses ; α-Interferon
Is Part Of: EMBO molecular medicine, 2016-09, Vol.8 (9), p.1099-1112
Description: 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. 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: England: John Wiley & Sons, Inc
Language: English
Identifier: ISSN: 1757-4676
EISSN: 1757-4684
DOI: 10.15252/emmm.201606413
PMID: 27520969
Source: GFMER Free Medical Journals
MEDLINE
PubMed Central
ProQuest Central
DOAJ Directory of Open Access Journals

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

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