IFN-γ Hinders Recovery from Mucosal Inflammation during Antibiotic Therapy for Salmonella Gut Infection

Summary 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 (ψ 50 : ∼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.