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

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. [Display omitted] •IFNλs are the first IFNs produced that suppress initial viral spread•IFNλs exhibit potent antiviral functions without activating inflammation•Type I IFNs come up later to enhance antiviral and pro-inflammatory responses•IFNλs and type I IFNs ensure optimal viral clearance with minimal collateral damage The importance of IFNλs in the respiratory tract remains puzzling. Galani and colleagues show that IFNλs provide front-line antiviral protection without activating inflammation. When infection escapes IFNλ control, type I IFNs come into play to enhance antiviral defenses and trigger pro-inflammatory responses essential for confronting infection but causing immunopathology.