title: IFN-γ Hinders Recovery from Mucosal Inflammation during Antibiotic Therapy for Salmonella Gut Infection.
abstract: Salmonella Typhimurium (S.Tm) causes acute enteropathy resolving after 4-7 days. Strikingly, antibiotic therapy does not accelerate disease resolution. We screened for factors blocking remission using a S.Tm enterocolitis model. The antibiotic ciprofloxacin clears pathogen stool loads within 3-24 hr, while gut pathology resolves more slowly (ψ50: ∼48 hr, remission: 6-9 days). This delayed resolution is mediated by an interferon-γ (IFN-γ)-dependent response that is triggered during acute infection and continues throughout therapy. Specifically, IFN-γ production by mucosal T and NK cells retards disease resolution by maintaining signaling through the transcriptional regulator STAT1 and boosting expression of inflammatory mediators like IL-1β, TNF, and iNOS. Additionally, sustained IFN-γ fosters phagocyte accumulation and hampers antimicrobial defense mediated by IL-22 and the lectin REGIIIβ. These findings reveal a role for IFN-γ in delaying resolution of intestinal inflammation and may inform therapies for acute Salmonella enteropathy, chronic inflammatory bowel diseases, or disease resolution during antibiotic treatment.
authors.affiliation: Institute of Microbiology, ETH Zurich, 8093 Zurich, Switzerland. Electronic address: dtamas@ethz.ch.
authors.forename: Tamas
authors.initials: T
authors.lastname: Dolowschiak
authors.affiliation: Institute of Microbiology, ETH Zurich, 8093 Zurich, Switzerland.
authors.forename: Anna Angelika
authors.initials: AA
authors.lastname: Mueller
authors.affiliation: Institute of Microbiology, ETH Zurich, 8093 Zurich, Switzerland.
authors.forename: Lynn Joanna
authors.initials: LJ
authors.lastname: Pisan
authors.affiliation: Department of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
authors.forename: Rounak
authors.initials: R
authors.lastname: Feigelman
authors.affiliation: Institute of Microbiology, ETH Zurich, 8093 Zurich, Switzerland.
authors.forename: Boas
authors.initials: B
authors.lastname: Felmy
authors.affiliation: Institute of Microbiology, ETH Zurich, 8093 Zurich, Switzerland.
authors.forename: Mikael Erik
authors.initials: ME
authors.lastname: Sellin
authors.affiliation: Institute of Virology, TU Munich, 81675 Munich, Germany.
authors.forename: Sukumar
authors.initials: S
authors.lastname: Namineni
authors.affiliation: Institute of Microbiology, ETH Zurich, 8093 Zurich, Switzerland.
authors.forename: Bidong Dinh
authors.initials: BD
authors.lastname: Nguyen
authors.affiliation: Institute of Microbiology, ETH Zurich, 8093 Zurich, Switzerland.
authors.forename: Sandra Yvonne
authors.initials: SY
authors.lastname: Wotzka
authors.affiliation: Institute of Virology, TU Munich, 81675 Munich, Germany; Division of Chronic Inflammation and Cancer, DKFZ, 69121 Heidelberg, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
authors.affiliation: Department of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: von Mering
authors.affiliation: Institute of Pathology, University of Bern, 3010 Bern, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Mueller
authors.affiliation: Institute of Microbiology, ETH Zurich, 8093 Zurich, Switzerland. Electronic address: hardt@micro.biol.ethz.ch.
authors.forename: Wolf-Dietrich
authors.initials: WD
authors.lastname: Hardt
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004760:Enterocolitis / Q000188:drug therapy / Q000276:immunology / Q000382:microbiology / Q000473:pathology*; D041981:Gastrointestinal Tract / Q000276:immunology / Q000382:microbiology / Q000473:pathology*; D007155:Immunologic Factors / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D007694:Killer Cells, Natural / Q000276:immunology; D008810:Mice, Inbred C57BL; D010586:Phagocytes / Q000276:immunology; D012480:Salmonella Infections / Q000188:drug therapy / Q000276:immunology / Q000382:microbiology / Q000473:pathology*; D012486:Salmonella typhimurium / Q000187:drug effects / Q000254:growth & development*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000900:Anti-Bacterial Agents; D007155:Immunologic Factors; D007371:Interferon-gamma