Epithelial type I interferon signaling in Salmonella typhimurium infection

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SUMMARY Cytokines are key mediators of inflammation and the host immune response. For many cytokines, signaling cascades are initiated by the binding of cytokines to their cognate receptor and the phosphorylation of Signal Transducers and Activators of Transcription (STAT) proteins by receptor bound Janus kinases (JAK). STAT proteins then form homo or heterodimer complexes, which translocate to the nucleus and regulate the transcription of multiple genes. Despite the high number of cytokines, there are only seven different STAT proteins that determine the fate of cytokine receptor signaling. Type I IFN signaling cascades begin following the binding of IFN/ to their cognate receptor (IFNAR). IFNAR activation leads to the formation of STAT1/STAT1 homodimers and STAT1/STAT2 heterodimers that each trigger distinct signaling cascades. Animals deficient in STAT1 signaling or IFNAR exhibit defects in inflammasome formation, caspase activation, and inflammatory cell death during infection with S. Typhimurium. However, it remains unclear whether genetic ablation of STAT1/STAT2 signaling alone changes the host response to Salmonella infection. The objectives of this application are to determine the mechanisms by which STAT2 dependent type I interferon signaling in epithelial cells contributes to intestinal inflammation that enables S. Typhimurium to outgrow the microbiota. Our central hypothesis that STAT2-dependent type I IFN signaling in epithelial cells leads to neutrophil recruitment, which in turn creates a microaerophilic and nitrate-rich environment enabling the luminal outgrowth of S. Typhimurium.