title: Expression ofIfnlr1on Intestinal Epithelial Cells Is Critical to the Antiviral Effects of Interferon Lambda against Norovirus and Reovirus.
abstract: Lambda interferon (IFN-λ) has potent antiviral effects against multiple enteric viral pathogens, including norovirus and rotavirus, in both preventing and curing infection. Because the intestine includes a diverse array of cell types, however, the cell(s) upon which IFN-λ acts to exert its antiviral effects is unclear. Here, we sought to identify IFN-λ-responsive cells by generation of mice with lineage-specific deletion of the receptor for IFN-λ,Ifnlr1We found that expression of IFNLR1 on intestinal epithelial cells (IECs) in the small intestine and colon is required for enteric IFN-λ antiviral activity. IECIfnlr1expression also determines the efficacy of IFN-λ in resolving persistent murine norovirus (MNoV) infection and regulates fecal shedding and viral titers in tissue. Thus, the expression ofIfnlr1by IECs is necessary for the response to both endogenous and exogenous IFN-λ. We further demonstrate that IECIfnlr1expression is required for the sterilizing innate immune effects of IFN-λ by extending these findings inRag1-deficient mice. Finally, we assessed whether our findings pertained to multiple viral pathogens by infecting mice specifically lacking IECIfnlr1expression with reovirus. These mice phenocopiedIfnlr1-null animals, exhibiting increased intestinal tissue titers and enhanced reovirus fecal shedding. Thus, IECs are the critical cell type responding to IFN-λ to control multiple enteric viruses. This is the first genetic evidence that supports an essential role for IECs in IFN-λ-mediated control of enteric viral infection, and these findings provide insight into the mechanism of IFN-λ-mediated antiviral activity.IMPORTANCEHuman noroviruses (HNoVs) are the leading cause of epidemic gastroenteritis worldwide. Type III interferons (IFN-λ) control enteric viral infections in the gut and have been shown to cure mouse norovirus, a small-animal model for HNoVs. Using a genetic approach with conditional knockout mice, we identified IECs as the dominant IFN-λ-responsive cells in control of enteric virus infectionin vivoUpon murine norovirus or reovirus infection,Ifnlr1depletion in IECs largely recapitulated the phenotype seen inIfnlr1-/-mice of higher intestinal tissue viral titers and increased viral shedding in the stool. Moreover, IFN-λ-mediated sterilizing immunity against murine norovirus requires the capacity of IECs to respond to IFN-λ. These findings clarify the mechanism of action of this cytokine and emphasize the therapeutic potential of IFN-λ for treating mucosal viral infections.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Megan T
authors.initials: MT
authors.lastname: Baldridge
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Sanghyun
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Judy J
authors.initials: JJ
authors.lastname: Brown
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: McAllister
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Urbanek
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.|Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Terence S
authors.initials: TS
authors.lastname: Dermody
authors.affiliation: Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon, USA nice@ohsu.edu virgin@wustl.edu.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Nice
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA nice@ohsu.edu virgin@wustl.edu.
authors.forename: Herbert W
authors.initials: HW
authors.lastname: Virgin
mesh_terms: D000818:Animals; D017250:Caliciviridae Infections / Q000276:immunology / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D007113:Immunity, Innate; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism; D007420:Intestine, Large / Q000276:immunology / Q000378:metabolism / Q000821:virology; D007421:Intestine, Small / Q000276:immunology / Q000378:metabolism / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D029322:Norovirus / Q000502:physiology*; D009928:Organ Specificity; D030102:Orthoreovirus, Mammalian / Q000502:physiology*; D017471:Receptors, Interferon / Q000378:metabolism*; D012088:Reoviridae Infections / Q000276:immunology / Q000378:metabolism / Q000821:virology; D017201:Virus Shedding
chemical_list: C000604340:IFNLR1 protein, mouse; D017471:Receptors, Interferon
keywords: innate immunity; interferons; mucosal immunity; norovirus; reovirus