Interferon-λ Mediates Non-redundant Front-Line Antiviral Protection against Influenza Virus Infection without Compromising Host Fitness

Ioanna E Galani; Vasiliki Triantafyllia; Evridiki-Evangelia Eleminiadou; Ourania Koltsida; Athanasios Stavropoulos; Maria Manioudaki; Dimitris Thanos; Sean E Doyle; Sergei V Kotenko; Kalliopi Thanopoulou; Evangelos Andreakos

doi:10.1016/j.immuni.2017.04.025

Interferon-λ Mediates Non-redundant Front-Line Antiviral Protection against Influenza Virus Infection without Compromising Host Fitness

Immunity. 2017 May 16;46(5):875-890.e6. doi: 10.1016/j.immuni.2017.04.025.

Affiliations

¹ Laboratory of Immunobiology, Center for Clinical, Experimental Surgery, and Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece.
² Laboratory of Molecular Biology, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece.
³ ZymoGenetics, Inc., A Bristol-Myers Squibb Company, Seattle, WA 98102, USA.
⁴ Department of Microbiology, Biochemistry, and Molecular Genetics, Center for Immunity and Inflammation, University Hospital Cancer Center, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA.
⁵ Laboratory of Immunobiology, Center for Clinical, Experimental Surgery, and Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece. Electronic address: [email protected].

PMID: 28514692
DOI: 10.1016/j.immuni.2017.04.025

Abstract

Lambda interferons (IFNλs) or type III IFNs share homology, expression patterns, signaling cascades, and antiviral functions with type I IFNs. This has complicated the unwinding of their unique non-redundant roles. Through the systematic study of influenza virus infection in mice, we herein show that IFNλs are the first IFNs produced that act at the epithelial barrier to suppress initial viral spread without activating inflammation. If infection progresses, type I IFNs come into play to enhance viral resistance and induce pro-inflammatory responses essential for confronting infection but causing immunopathology. Central to this are neutrophils which respond to both cytokines to upregulate antimicrobial functions but exhibit pro-inflammatory activation only to type I IFNs. Accordingly, Ifnlr1^-/- mice display enhanced type I IFN production, neutrophilia, lung injury, and lethality, while therapeutic administration of PEG-IFNλ potently suppresses these effects. IFNλs therefore constitute the front line of antiviral defense in the lung without compromising host fitness.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cluster Analysis
Cytokines / biosynthesis
Disease Models, Animal
Disease Resistance / genetics
Disease Resistance / immunology
Female
Gene Expression
Gene Expression Profiling
Genes, Reporter
Genetic Fitness*
Host-Pathogen Interactions*
Humans
Inflammation Mediators / metabolism
Influenza A virus / genetics
Influenza A virus / immunology*
Influenza, Human / drug therapy
Influenza, Human / immunology*
Influenza, Human / metabolism*
Influenza, Human / virology
Interferon-gamma / genetics
Interferon-gamma / metabolism*
Interferon-gamma / pharmacology
Lung / immunology
Lung / metabolism
Lung / pathology
Lung / virology
Male
Mice
Mice, Knockout
Neutrophils / immunology
Neutrophils / metabolism
Orthomyxoviridae Infections / immunology
Orthomyxoviridae Infections / metabolism
Orthomyxoviridae Infections / mortality
Orthomyxoviridae Infections / virology
Respiratory Mucosa / immunology
Respiratory Mucosa / metabolism
Respiratory Mucosa / pathology
Respiratory Mucosa / virology
Viral Load
Virus Replication

Substances

Cytokines
Inflammation Mediators
Interferon-gamma