New paper by the Hardt Lab
IFN-γ Hinders Recovery from Mucosal Inflammation during Antibiotic Therapy for Salmonella Gut Infection
Tamas Dolowschiak, Anna A. Müller, Lynn J. Pisan, Rounak Feigelman, Boas Felmy, Mikael E. Sellin, Sukumar Namineni, Bidong Nguyen, Sandra Y. Wotzka, Mathias Heikenwälder, Christian von Mering, Christoph Müller, Wolf-Dietrich Hardt.
Cell Host & Microbe. 2016 Aug 10;20, 238–249.
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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.