title: Type I interferons link viral infection to enhanced epithelial turnover and repair.
abstract: The host immune system functions constantly to maintain chronic commensal and pathogenic organisms in check. The consequences of these immune responses on host physiology are as yet unexplored, and may have long-term implications in health and disease. We show that chronic viral infection increases epithelial turnover in multiple tissues, and the antiviral cytokines type I interferons (IFNs) mediate this response. Using a murine model with persistently elevated type I IFNs in the absence of exogenous viral infection, the Irgm1(-/-) mouse, we demonstrate that type I IFNs act through nonepithelial cells, including macrophages, to promote increased epithelial turnover and wound repair. Downstream of type I IFN signaling, the highly related IFN-stimulated genes Apolipoprotein L9a and b activate epithelial proliferation through ERK activation. Our findings demonstrate that the host immune response to chronic viral infection has systemic effects on epithelial turnover through a myeloid-epithelial circuit.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Lulu
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyoshi
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Sofia
authors.initials: S
authors.lastname: Origanti
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Nice
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Alexandra C
authors.initials: AC
authors.lastname: Barger
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Manieri
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Fogel
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: French
authors.affiliation: Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: David
authors.initials: D
authors.lastname: Piwnica-Worms
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Piwnica-Worms
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Herbert W
authors.initials: HW
authors.lastname: Virgin
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Lenschow
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: stappenb@pathology.wustl.edu.
authors.forename: Thaddeus S
authors.initials: TS
authors.lastname: Stappenbeck
mesh_terms: D000818:Animals; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology*; D004848:Epithelium / Q000276:immunology* / Q000502:physiology; D005260:Female; D019204:GTP-Binding Proteins / Q000172:deficiency; D020869:Gene Expression Profiling; D007370:Interferon Type I / Q000378:metabolism*; D008297:Male; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D014777:Virus Diseases / Q000276:immunology*
chemical_list: C096000:Ifi1 protein, mouse; D007370:Interferon Type I; D019204:GTP-Binding Proteins