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

Area of Science:

• Immunology
• Microbiology
• Gastroenterology

Background:

• Salmonella Typhimurium (S.Tm) infection causes acute enteropathy that typically resolves in 4-7 days.
• Antibiotic treatment effectively reduces S.Tm stool loads but does not accelerate the resolution of gut pathology.

Purpose of the Study:

• To identify factors that impede the resolution of S.Tm-induced enterocolitis despite antibiotic treatment.
• To elucidate the mechanisms by which interferon-gamma (IFN-γ) delays intestinal inflammation recovery.

Main Methods:

• Utilized a mouse model of S.Tm enterocolitis.
• Administered ciprofloxacin to assess pathogen clearance and disease resolution timelines.
• Measured IFN-γ levels and downstream signaling pathways (STAT1).
• Assessed inflammatory mediators (IL-1β, TNF, iNOS) and antimicrobial factors (IL-22, REGIIIβ).

Main Results:

• Ciprofloxacin rapidly cleared S.Tm from stool, but gut pathology resolution took significantly longer (6-9 days).
• Delayed resolution was dependent on interferon-gamma (IFN-γ), triggered during infection and persisting through antibiotic therapy.
• IFN-γ from mucosal T and NK cells sustained STAT1 signaling, increased inflammatory mediators, and impaired protective IL-22 and REGIIIβ responses.
• Sustained IFN-γ also promoted phagocyte accumulation, further hindering recovery.

Conclusions:

• Interferon-gamma plays a critical role in delaying the resolution of intestinal inflammation during Salmonella enteropathy, even with antibiotic intervention.
• Understanding the IFN-γ-mediated pathways offers potential therapeutic targets for accelerating recovery from acute Salmonella infections.
• These findings may also have implications for managing chronic inflammatory bowel diseases and improving outcomes during antibiotic treatment for other enteric infections.