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.

Plasma-Derived Polyreactive Secretory-Like IgA and IgM Opsonizing Salmonella enterica Typhimurium Reduces Invasion and Gut Tissue Inflammation through Agglutination

“…The effect was less pronounced in presence of IgA/M. The data suggest that keeping St away from the gastrointestinal epithelium ensures protection in a context which does not need to rely on exacerbated inflammatory responses ( 25 ).…”

Recurrent infection progressively disables host protection against intestinal inflammation

“…The degree of this persistence may be determined in part by initial infection titers and the time between recurrent infections, and may result from multiple mechanisms. One possibility is the generation of epigenetic modifications to inflammatory gene promoters regulated by Tlr4 function that result in the persistence of inflammatory cytokine expression and may explain observations of the slow resolution of inflammatory processes (36, 37). The enterocyte Neu3 allele is perhaps similarly regulated in this way as its expression remained induced long after periodic ST infections were discontinued.…”

Intestinal restriction of Salmonella Typhimurium requires caspase-1 and caspase-11 epithelial intrinsic inflammasomes

“…stages of Salmonella-induced colitis and has been described as an early stage effector cytokine with high systemically circulating levels during the first day of oral infection [13,14]. When we analyzed cecal tissues collected from streptomycin-pretreated uninfected and S. Typhimurium-infected mice at 18 h and 72 h p.i.…”

“…However, the impact of IFN-γ on pathogen burdens and mucosal inflammation is not evident until 48 h p.i. [13,14,28]. Acute sources of IFN-γ include innate lymphoid cells, NK cells, neutrophils and intestinal intraepithelial lymphocytes [13,14,[28][29][30][31].…”

“…[13,14,28]. Acute sources of IFN-γ include innate lymphoid cells, NK cells, neutrophils and intestinal intraepithelial lymphocytes [13,14,[28][29][30][31]. Interestingly, Songhet et al observed that control over S. Typhimurium burdens within IECs was IFN-γ dependent, and although bone marrow-derived IFN-γR signaling controlled systemic spread, stromal IFN-γR expression was required for this control in IECs [28].…”