title: IFN-lambda determines the intestinal epithelial antiviral host defense.
abstract: Type I and type III IFNs bind to different cell-surface receptors but induce identical signal transduction pathways, leading to the expression of antiviral host effector molecules. Despite the fact that type III IFN (IFN-λ) has been shown to predominantly act on mucosal organs, in vivo infection studies have failed to attribute a specific, nonredundant function. Instead, a predominant role of type I IFN was observed, which was explained by the ubiquitous expression of the type I IFN receptor. Here we comparatively analyzed the role of functional IFN-λ and type I IFN receptor signaling in the innate immune response to intestinal rotavirus infection in vivo, and determined viral replication and antiviral gene expression on the cellular level. We observed that both suckling and adult mice lacking functional receptors for IFN-λ were impaired in the control of oral rotavirus infection, whereas animals lacking functional receptors for type I IFN were similar to wild-type mice. Using Mx1 protein accumulation as marker for IFN responsiveness of individual cells, we demonstrate that intestinal epithelial cells, which are the prime target cells of rotavirus, strongly responded to IFN-λ but only marginally to type I IFN in vivo. Systemic treatment of suckling mice with IFN-λ repressed rotavirus replication in the gut, whereas treatment with type I IFN was not effective. These results are unique in identifying a critical role of IFN-λ in the epithelial antiviral host defense.
authors.affiliation: Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Pott
authors.forename: Tanel
authors.initials: T
authors.lastname: Mahlakõiv
authors.forename: Markus
authors.initials: M
authors.lastname: Mordstein
authors.forename: Claudia U
authors.initials: CU
authors.lastname: Duerr
authors.forename: Thomas
authors.initials: T
authors.lastname: Michiels
authors.forename: Silvia
authors.initials: S
authors.lastname: Stockinger
authors.forename: Peter
authors.initials: P
authors.lastname: Staeheli
authors.forename: Mathias W
authors.initials: MW
authors.lastname: Hornef
mesh_terms: D000818:Animals; D016207:Cytokines / Q000276:immunology*; D007113:Immunity, Innate; D007413:Intestinal Mucosa / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D012401:Rotavirus / Q000276:immunology / Q000502:physiology; D012400:Rotavirus Infections / Q000276:immunology / Q000473:pathology / Q000517:prevention & control / Q000821:virology; D015398:Signal Transduction / Q000276:immunology; D014779:Virus Replication; D007378:Interleukins; D000095022:Interferon Lambda
chemical_list: D016207:Cytokines; D053633:Receptor, Interferon alpha-beta; C508032:Ifnar1 protein, mouse; C511668:interferon-lambda protein, mouse; D007378:Interleukins; D000095022:Interferon Lambda