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

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 (Psi(50): similar to 48 hr, remission: 6-9 days). This delayed resolution is mediated by an interferon-gamma (IFN-gamma)-dependent response that is triggered during acute infection and continues throughout therapy. Specifically, IFN-gamma 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-1 beta, TNF, and iNOS. Additionally, sustained IFN-gamma fosters phagocyte accumulation and hampers antimicrobial defense mediated by IL-22 and the lectin REGIII beta. These findings reveal a role for IFN-gamma in delaying resolution of intestinal inflammation and may inform therapies for acute Salmonella enteropathy, chronic inflammatory bowel diseases, or disease resolution during antibiotic treatment.